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

• Sponsor: Russian Academy of Medical Sciences (Other)
• Overall Status: Completed
• CT.gov ID: NCT02957123
• Collaborator: (none)
• Enrollment: 30
• Location: 1
• Arm: 1
• Actual Duration (Months): 54
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• 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: Mar 1, 2016
• Actual Primary Completion Date: Sep 1, 2020
• Actual Study Completion Date: Sep 1, 2020

Arms and Interventions

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 Names: Bioactive Factors, Produced by M2 Macrophage

Outcome Measures

Primary Outcome Measures

1. The Number of Patients With Severe Adverse Events and Adverse Reactions [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) [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) [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 [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) [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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Institute of Fundamental and Clinical Immunology	Novosibirsk		Russian Federation	630099

Sponsors and Collaborators

• Russian Academy of Medical Sciences

Investigators

• 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)

• Study Protocol - Oct 11, 2015
• Informed Consent Form - Oct 11, 2015
• Statistical Analysis Plan - Oct 11, 2015

More Information

Additional Information:

• Manuscript with study results

Publications

• Chernykh ER, Kafanova MY, Shevela EY, Sirota SI, Adonina EI, Sakhno LV, Ostanin AA, Kozlov VV. Clinical experience with autologous M2 macrophages in children with severe cerebral palsy. Cell Transplant. 2014;23 Suppl 1:S97-104. doi: 10.3727/096368914X684925. Epub 2014 Oct 9.
• Chernykh ER, Shevela EY, Sakhno LV, Tikhonova MA, Petrovsky YL, Ostanin AA. The generation and properties of human M2-like macrophages: potential candidates for CNS repair? Cell Ther Transplant., 2010 DOI: 10.3205/ctt-2010-en-000080.01
• Chernykh ER, Shevela EY, Starostina NM, Morozov SA, Davydova MN, Menyaeva EV, Ostanin AA. Safety and Therapeutic Potential of M2 Macrophages in Stroke Treatment. Cell Transplant. 2016;25(8):1461-71. doi: 10.3727/096368915X690279. Epub 2015 Dec 14.
• Sakhno LV, Shevela EY, Tikhonova MA, Ostanin AA, Chernykh ER. The Phenotypic and Functional Features of Human M2 Macrophages Generated Under Low Serum Conditions. Scand J Immunol. 2016 Feb;83(2):151-9. doi: 10.1111/sji.12401.

• 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: Nov 6, 2016
• Last Update Posted: Feb 18, 2021
• Last Verified: Feb 1, 2021

• Keywords provided by Alexander A Ostanin, Head of Clinical Department, Russian Academy of Medical Sciences: macrophages M2 type; cytokines; intranasal administration; neuroprotection; neuroregeneration; organic brain syndrome; neurocognitive disorders
• Additional relevant MeSH terms: Brain Diseases; Brain Ischemia; Chronic Traumatic Encephalopathy; Disease; Syndrome; Mental Disorders; Psychotic Disorders; Neurocognitive Disorders; Cognition Disorders

Study Results

Participant Flow

Arm/Group Title	Intranasal Auto-M2-BFs
Arm/Group Description	Intranasally-Administered Bioactive Factors (BF), Produced by Autologous M2 Macrophage (auto-M2-BFs). 30 patients with organic brain syndrome will receive auto-M2-BFs as intranasal inhalations with the aerosol inhaler device (nebulizer), 2.0 mL once a day up to 30 days.
Period Title: Overall Study
STARTED	30
COMPLETED	30
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Intranasal Auto-M2-BFs
Arm/Group Description	Intranasally-Administered Bioactive Factors, Produced by Autologous M2 Macrophage (auto-M2-BFs). 30 patients with organic brain syndrome will receive auto-M2-BFs as intranasal inhalations with the aerosol inhaler device (nebulizer), 2.0 mL once a day up to 30 days.
Overall Participants	30
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	16 53.3%
>=65 years	14 46.7%
Sex: Female, Male (Count of Participants)
Female	19 63.3%
Male	11 36.7%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (Count of Participants)
Russia	30 100%

Outcome Measures

1. Primary Outcome

Title	The Number of Patients With Severe Adverse Events and Adverse Reactions
Description	Occurrence of severe adverse events and adverse reactions (allergic, toxic, inflammatory reactions; neurological deterioration, convulsive syndrome)
Time Frame	up to 6 months after treatment

Outcome Measure Data

Analysis Population Description

The number of patients with severe adverse events and adverse reactions

Arm/Group Title	Intranasal Auto-M2-BFs
Arm/Group Description	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 their first doses (n=2-3) of auto-M2-BFs in clinic and wait 2 hrs to determine any short-time adverse effects of inhaled dose. The subsequent course of intranasal inhalations (once a day up to 30 days) performed as outpatient treatment. Intranasal auto-M2-BFs: Delivery is performed with the aerosol inhaler device (nebulizer), 2.0 mL once a day up to 30 days.
Measure Participants	30
Count of Participants [Participants]	0 0%

2. Secondary Outcome

Title	Change in Subjective Assessment of Clinical Symptoms (SACS)
Description	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.
Time Frame	Baseline and 6 months after treatment

Outcome Measure Data

Analysis Population Description

Patients with neurological improvements are assessed by SACS "total" score as > 6 points' reduction from baseline.

Arm/Group Title	Intranasal Auto-M2-BFs
Arm/Group Description	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 their first doses (n=2-3) of auto-M2-BFs in clinic and wait 2 hrs to determine any short-time adverse effects of inhaled dose. The subsequent course of intranasal inhalations (once a day up to 30 days) performed as outpatient treatment. Intranasal auto-M2-BFs: Delivery is performed with the aerosol inhaler device (nebulizer), 2.0 mL once a day up to 30 days.
Measure Participants	30
Count of Participants [Participants]	12 40%

3. Secondary Outcome

Title	Change in Hospital Anxiety and Depression Scale (HADS)
Description	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.
Time Frame	Baseline and 6 months after treatment

Outcome Measure Data

Analysis Population Description

Improvements in patients with anxiety/depression symptoms are assessed by HADS "total" score as > 4 points reduction from baseline.

Arm/Group Title	Intranasal Auto-M2-BFs
Arm/Group Description	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 their first doses (n=2-3) of auto-M2-BFs in clinic and wait 2 hrs to determine any short-time adverse effects of inhaled dose. The subsequent course of intranasal inhalations (once a day up to 30 days) performed as outpatient treatment. Intranasal auto-M2-BFs: Delivery is performed with the aerosol inhaler device (nebulizer), 2.0 mL once a day up to 30 days.
Measure Participants	26
Count of Participants [Participants]	14 46.7%

4. Secondary Outcome

Title	Change in Functional Mobility Assessment (FMA) Scale
Description	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.
Time Frame	Baseline and 6 months after treatment

Outcome Measure Data

Analysis Population Description

Improved mobility is assessed as FMA "total" score enhancement > 4 points from baseline.

Arm/Group Title	Intranasal Auto-M2-BFs
Arm/Group Description	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 their first doses (n=2-3) of auto-M2-BFs in clinic and wait 2 hrs to determine any short-time adverse effects of inhaled dose. The subsequent course of intranasal inhalations (once a day up to 30 days) performed as outpatient treatment. Intranasal auto-M2-BFs: Delivery is performed with the aerosol inhaler device (nebulizer), 2.0 mL once a day up to 30 days.
Measure Participants	28
Count of Participants [Participants]	16 53.3%

5. Secondary Outcome

Title	Change in Montreal Cognitive Assessment (МоСА)
Description	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.
Time Frame	Baseline and 6 months after treatment

Outcome Measure Data

Analysis Population Description

Improvements in patients with cognitive disorder are assessed as MoCA MoCA "total" score increase > 3 points from baseline.

Arm/Group Title	Intranasal Auto-M2-BFs
Arm/Group Description	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 their first doses (n=2-3) of auto-M2-BFs in clinic and wait 2 hrs to determine any short-time adverse effects of inhaled dose. The subsequent course of intranasal inhalations (once a day up to 30 days) performed as outpatient treatment. Intranasal auto-M2-BFs: Delivery is performed with the aerosol inhaler device (nebulizer), 2.0 mL once a day up to 30 days.
Measure Participants	19
Count of Participants [Participants]	10 33.3%

Adverse Events

Time Frame	The severe adverse events and adverse reactions (allergic, toxic, inflammatory reactions; neurological deterioration, convulsive syndrome) were collected up to 6 months after treatment
Arm/Group Title	Intranasal Auto-M2-BFs
Arm/Group Description	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 their first doses (n=2-3) of auto-M2-BFs in clinic and wait 2 hrs to determine any short-time adverse effects of inhaled dose. The subsequent course of intranasal inhalations (once a day up to 30 days) performed as outpatient treatment. Intranasal auto-M2-BFs: Delivery is performed with the aerosol inhaler device (nebulizer), 2.0 mL once a day up to 30 days.
All Cause Mortality
	Intranasal Auto-M2-BFs
	Affected / at Risk (%)	# Events
Total	0/30 (0%)
Serious Adverse Events
	Intranasal Auto-M2-BFs
	Affected / at Risk (%)	# Events
Total	0/30 (0%)
Other (Not Including Serious) Adverse Events
	Intranasal Auto-M2-BFs
	Affected / at Risk (%)	# Events
Total	0/30 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.