Organic Brain Syndrome, NonpsychoticPhase 1/2NCT02957123
Intranasal Inhalations of Bioactive Factors Produced by M2 Macrophages in Patients With Organic Brain Syndrome
A Phase 1/2 study testing Intranasal auto-M2-BFs in people with Organic Brain Syndrome, Nonpsychotic and Neurocognitive Disorders, run by Russian Academy of Medical Sciences at 1 site in Russia.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Organic Brain Syndrome, Nonpsychotic, Neurocognitive Disorders, Mental Disorder, Organic
- What is being tested?
- Intranasal auto-M2-BFs
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 1 siteRussia
- Study dates
- Mar 2016to Sep 2020
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- Psychiatric disorders
- Seizures
- Severe dementia
- Hepatic or renal dysfunctions
- Hemodynamic or respiratory instability
- HIV or uncontrolled bacterial, fungal, or viral infections
Show all 10Show fewer
- Pregnancy
- Malignancy
- Intolerance to gentamicin and / or multiple drug allergies
- Participation in other clinical trials
Trial locations and contacts
1 site in 1 country.
Russia1 site
Institute of Fundamental and Clinical Immunology
Novosibirsk, 630099
About this study
Official title: Safety/Efficacy of Intranasally-Administered Bioactive Factors Produced by Autologous 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).
Read the 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.
- Conditions
- Organic Brain Syndrome, Nonpsychotic, Neurocognitive Disorders, Mental Disorder, Organic, Delirium, Dementia, Amnestic, Cognitive Disorders, Nonpsychotic Organic Brain Syndrome, Organic Mental Disorder
- Being tested
- Intranasal auto-M2-BFs
- Keywords
- macrophages M2 type, cytokines, intranasal administration, neuroprotection, neuroregeneration, organic brain syndrome, neurocognitive disorders
- Medical subject headings
- Neurocognitive Disorders, Chronic Traumatic Encephalopathy, Brain Ischemia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Intranasal auto-M2-BFsDrug
Also called Bioactive Factors, Produced by M2 Macrophage
Delivery is performed with the aerosol inhaler device (nebulizer), 2.0 mL once a day up to 30 days.
| Study group | Role | What they receive |
|---|---|---|
| Intranasal auto-M2-BFs | Experimental | 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. Receives: Drug: Intranasal auto-M2-BFs |
What is being measured
The primary outcome is the main question the study is designed to answer.
The Number of Patients With Severe Adverse Events and Adverse Reactions
Occurrence of severe adverse events and adverse reactions (allergic, toxic, inflammatory reactions; neurological deterioration, convulsive syndrome)
Measured: up to 6 months after treatment
Secondary outcomes (4)
Change in Subjective Assessment of Clinical Symptoms (SACS)
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.
Measured: Baseline and 6 months after treatment
Change in Hospital Anxiety and Depression Scale (HADS)
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.
Measured: Baseline and 6 months after treatment
Change in Functional Mobility Assessment (FMA) Scale
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.
Measured: Baseline and 6 months after treatment
Change in Montreal Cognitive Assessment (МоСА)
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.
Measured: Baseline and 6 months after treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Nov 2016 (estimated)
- Study startMar 2016
- Primary completionSep 2020
- Study completionSep 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Organic Brain Syndrome, NonpsychoticStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- Russian Academy of Medical Sciences
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Alexander A Ostanin, Russian Academy of Medical Sciences
- Investigators
- Elena R Chernykh, MD, PhD, Study chair, Institute of Fundamental and Clinical ImmunologyAlexander A Ostanin, MD, PhD, Principal investigator, Institute of Fundamental and Clinical Immunology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02957123
- Sponsor's protocol ID
- IFCI-25/05/2015
- Status last verified
- Feb 2021
- First submitted
- 3 Nov 2016
- Last updated
- 18 Feb 2021
- Results posted
- Yes, on ClinicalTrials.gov
Publications
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
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.
PubMed 26678544Chernykh 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.
PubMed 25302537Chernykh 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.
PubMed 26671426Shevela 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
Study at a glance
From the registry record, last updated by the sponsor on 18 Feb 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Safety/Efficacy of Intranasally-Administered Bioactive Factors Produced by Autologous M2 Macrophages in Patients With Organic Brain Syndrome
- ClinicalTrials.gov ID
- NCT02957123
- Acronym / sponsor ID
- IFCI-25/05/2015
- Conditions
- Organic Brain Syndrome, Nonpsychotic, Neurocognitive Disorders, Mental Disorder, Organic, Delirium, Dementia, Amnestic, Cognitive Disorders, Nonpsychotic Organic Brain Syndrome, Organic Mental Disorder
- Keywords
- macrophages M2 type, cytokines, intranasal administration, neuroprotection, neuroregeneration, organic brain syndrome, neurocognitive disorders
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- Russian Academy of Medical SciencesUniversity, hospital or other
- Study start
- Mar 2016 (actual)
- Primary completion
- Sep 2020 (actual)
- Study completion
- Sep 2020 (actual)
- First posted
- 7 Nov 2016 (estimated)
- Results
- Posted 18 Feb 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
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
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Intranasal auto-M2-BFs | Experimental | Drug: Intranasal auto-M2-BFsIntranasally-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. |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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
Key exclusion criteria (10 listed)
- Psychiatric disorders
- Seizures
- Severe dementia
- Hepatic or renal dysfunctions
- Hemodynamic or respiratory instability
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Intranasal auto-M2-BFsAlso: Bioactive Factors, Produced by M2 MacrophageDelivery is performed with the aerosol inhaler device (nebulizer), 2.0 mL once a day up to 30 days. | Drug | Intranasal auto-M2-BFs |
Primary outcome
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)
4 secondary outcomes
Change in Subjective Assessment of Clinical Symptoms (SACS)
Time frame: Baseline and 6 months after treatment
Change in Hospital Anxiety and Depression Scale (HADS)
Time frame: Baseline and 6 months after treatment
Change in Functional Mobility Assessment (FMA) Scale
Time frame: Baseline and 6 months after treatment
Change in Montreal Cognitive Assessment (МоСА)
Time frame: Baseline and 6 months after treatment
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Feb 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- BackgroundChernykh 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
- Background: PubMed 26678544Sakhno 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.
- Background: PubMed 25302537Chernykh 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.
- Background: PubMed 26671426Chernykh 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.
- Results publicationShevela 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
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Elena R Chernykh, MD, PhD study chair
Institute of Fundamental and Clinical Immunology
Alexander A Ostanin, MD, PhD principal investigator
Institute of Fundamental and Clinical Immunology
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Intranasal auto-M2-BFs in people with Organic Brain Syndrome, Nonpsychotic and Neurocognitive Disorders, run by Russian Academy of Medical Sciences at 1 site in Russia.
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 3 inclusion and 10 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: finished, as of the sponsor's last update on 18 Feb 2021. 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 Russia. 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.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 18 Feb 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
The Number of Patients With Severe Adverse Events and Adverse Reactions (time frame: up to 6 months after treatment). 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 NCT02957123, which also lists 5 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 18 Feb 2021.