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NCT Number: NCT02957123

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

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).

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Key information

Conditions

Organic Brain Syndrome, Nonpsychotic Brain Damage, Chronic Brain Diseases Brain Injuries Brain Injuries, Traumatic Brain Injury, Chronic Brain Ischemia Cardiovascular Diseases Central Nervous System Diseases Cerebrovascular Disorders Chronic Disease Chronic Traumatic Encephalopathy Craniocerebral Trauma Delirium, Dementia, Amnestic, Cognitive Disorders Disease Attributes Encephalopathy, Ischemic Encephalopathy, Post-Traumatic, Chronic Mental Disorder, Organic Mental Disorders Nervous System Diseases Neurocognitive Disorders Neurodegenerative Diseases Nonpsychotic Organic Brain Syndrome Organic Mental Disorder Pathologic Processes Pathological Conditions, Signs and Symptoms Trauma, Nervous System Vascular Diseases Wounds and Injuries

Age range

18 year–80 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

Institute of Fundamental and Clinical Immunology

Novosibirsk, 630099, Russia

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Intranasal auto-M2-BFs

Drug

Delivery is performed with the aerosol inhaler device (nebulizer), 2.0 mL once a day up to 30 days.

Other names: Bioactive Factors, Produced by M2 Macrophage

Primary outcomes

  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 outcomes

  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.

Sponsors and collaborators

Lead sponsor

Russian Academy of Medical Sciences

Other

Registry information

Official study title

Safety/Efficacy of Intranasally-Administered Bioactive Factors Produced by Autologous M2 Macrophages in Patients With Organic Brain Syndrome

Important dates

Study start
2016
Primary completion
2020
Study completion
2020
First posted
Nov 7, 2016
Registry last updated
Feb 18, 2021

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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