Language DelayPhase 1/2NCT04689282
Intranasal Inhalations of M2 Macrophage Soluble Factors in Children With Developmental Speech Disorders
A Phase 1/2 study testing Bioactive Factors, Produced by M2 Type Macrophages (M2-BFs). in people with Language Delay and Language; Developmental Disorder, Expressive, 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 speech difficulties in children with developmental dysphasia (DD) are improved with intranasal inhalations of bioactive factors (BF), produced by macrophages of M2 phenotype (M2-BFs). Read more about this study
- Who is it for?
- Ages 3 to 18 years
- Conditions the study is for
- Language Delay, Language; Developmental Disorder, Expressive, Language; Developmental Disorder, Receptive
- What is being tested?
- Bioactive Factors, Produced by M2 Type Macrophages (M2-BFs).
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 14 participants
- Where
- 1 siteRussia
- Study dates
- 1 Feb 2020to 1 Sep 2021
- Phase
- Phase 1/2
- 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 3 to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- Age 3-18
- Speech disorders verified by speech therapist and neurologist
- Adequate hearing/vision to follow conversation
- Russian speaker
- A written informed consent of the parents/close relatives
Who cannot join
- Acute infectious disease (bacterial, fungal, or viral)
- Seizures
- 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 M2 Type Macrophages in Children With Developmental Speech Disorders
The investigators have designed an innovative proof-of-concept trial designed to provide data as to whether the speech difficulties in children with developmental dysphasia (DD) are improved with intranasal inhalations of bioactive factors (BF), produced by macrophages of M2 phenotype (M2-BFs). The rationale for this approach is the ability of central nervous system (CNS) to repair and the important role of macrophages in the regulation of this process. It was found that type 2 macrophages (M2) have anti-inflammatory and neurorestorative potential, in contrast to pro-inflammatory and neurotoxic effects of М1 cells. The influence of M2 is largely realized through the production of a wide spectrum 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 M2-BFs, as therapeutic tool, and intranasal administration focusing on nose to brain transport, as a mode of delivery. Expected clinical effects in treated children: improvement of speech understanding, word formation, grammatical structure of speech and formation of coherent speech.
Read the detailed description
Neuroinflammation plays a central role in the pathogenesis of any damage to the central nervous system (CNS) profoundly affecting the ability of neural cells to survive and to regenerate. Macrophages play a key role in the regulation of neuroinflammation, but their role is ambiguous. In fact, macrophages can both induce neuronal and glial toxicity and promote tissue repair. The opposite effects of macrophages are largely due to their plasticity and functional heterogeneity. Thus, classical pro-inflammatory macrophages (M1) are tissue-destructive, while anti-inflammatory (M2) macrophages mediate tissue repair. In addition, M2 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]. The data indicate that M2, in contrast to pro-inflammatory M1, 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 high IL-10 level. M2 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.
Pilot clinical trials have demonstrated the safety and clinical efficacy of intrathecal administration of M2 in children with severe cerebral palsy [2, 3] and in nonacute stroke patients [4]. Moreover, intranasal delivery of M2 macrophage-derived soluble products reduces neuropsychological deficit in patients with cerebrovascular disease [5]. Given this data, the investigators expect that intranasal administration of the M2-BFs (Bioactive Factors) will reduce the severity of speech disorders in children, including improving speech understanding, sensorimotor speech level, word formation skills, as well as the formation of the grammatical structure of speech and coherent speech. Of note, intranasal administration of M2 soluble factors allow to delivery bioactive agents to brain through the olfactory and trigeminal ways across brain-blood barrier.
- Conditions
- Language Delay, Language; Developmental Disorder, Expressive, Language; Developmental Disorder, Receptive, Autism Spectrum Disorder, Attention Deficit-Hyperactivity Disorder, Speech Disorders in Children
- Being tested
- Bioactive Factors, Produced by M2 Type Macrophages (M2-BFs).
- Keywords
- M2 type macrophages, Cytokines, Intranasal administration, Neuroprotection, neuroregeneration, Speech disorders
- Medical subject headings
- Language Development Disorders, Language, Developmental Disabilities, Autism Spectrum Disorder, Attention Deficit Disorder with Hyperactivity, Speech Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Bioactive Factors, Produced by M2 Type Macrophages (M2-BFs).Biological
Intranasal delivery of M2-BFs 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 M2-BFs | Experimental | Intranasally-Administered Bioactive Factors, Produced by M2 Type Macrophages (M2-BFs). M2 were generated in vitro from peripheral blood of a parent during 7 days. Cell-free culture medium, containing M2-BFs, was collected, and aliquots of 2 mL/vial were cryopreserved.
30 children with speech disorders will receive their first doses (n=2-3) of 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. Receives: Biological: Bioactive Factors, Produced by M2 Type Macrophages (M2-BFs). |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in the severity of speech disorders according to Speech Assessment Scale (SAS)
Speech Assessment Scale (SAS) is used to assess language development in children in six functional domains: Speech Comprehension; Sensomotor speech level; Grammatical structure of speech and inflection; Vocabulary and vocabulary skills; Connected speech; Gross and fine motor skills. Max total score:160 points (units of scale). Clinical improvement is manifested in an enhancement in the SAS score.
Measured: Baseline and 6 months after treatment
Secondary outcomes (1)
The number of patients with adverse events
Occurrence of adverse events including allergic, toxic, inflammatory reactions; neurological worsening; seizures
Measured: up to 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 posted30 Dec 2020
- Study start1 Feb 2020
- Primary completion1 Sep 2021
- Study completion1 Sep 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Language DelayStudies 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
- 14 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
- NCT04689282
- Sponsor's protocol ID
- IFCI-23/06/2017
- Status last verified
- Apr 2022
- First submitted
- 23 Dec 2020
- Last updated
- 2 May 2022
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
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 EYa, Kafanova MYu, Sakhno LV, Polovnikov EV, Ostanin AA. Monocyte-derived macrophages for treatment of cerebral palsy: a study of 57 cases. J Neurorestoratology. 2018; 6: 41-47. doi.org/10.2147/JN.S158843
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.
PubMed 26671426Shevela E, Davydova M, Starostina N, Yankovskaya A, Ostanin A, Chernykh E. Intranasal delivery of M2 macrophage-derived soluble products reduces neuropsychological deficit in patients with cerebrovascular disease: a pilot study. J 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 2 May 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Safety/Efficacy of Intranasally-Administered Bioactive Factors Produced by M2 Type Macrophages in Children With Developmental Speech Disorders
- ClinicalTrials.gov ID
- NCT04689282
- Acronym / sponsor ID
- IFCI-23/06/2017
- Conditions
- Language Delay, Language; Developmental Disorder, Expressive, Language; Developmental Disorder, Receptive, Autism Spectrum Disorder, Attention Deficit-Hyperactivity Disorder, Speech Disorders in Children
- Keywords
- M2 type macrophages, Cytokines, Intranasal administration, Neuroprotection, neuroregeneration, Speech disorders
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 14 participants (actual)
- Lead sponsor
- Russian Academy of Medical SciencesUniversity, hospital or other
- Study start
- 1 Feb 2020 (actual)
- Primary completion
- 1 Sep 2021 (actual)
- Study completion
- 1 Sep 2021 (actual)
- First posted
- 30 Dec 2020 (actual)
- Results
- Not posted in the source record
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 speech difficulties in children with developmental dysphasia (DD) are improved with intranasal inhalations of bioactive factors (BF), produced by macrophages of M2 phenotype (M2-BFs). The rationale for this approach is the ability of central nervous system (CNS) to repair and the important role of macrophages in the regulation of this process. It was found that type 2 macrophages (M2) have anti-inflammatory and neurorestorative potential, in contrast to pro-inflammatory and neurotoxic effects of М1 cells. The influence of M2 is largely realized through the production of a wide spectrum 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 M2-BFs, as therapeutic tool, and intranasal administration focusing on nose to brain transport, as a mode of delivery. Expected clinical effects in treated children: improvement of speech understanding, word formation, grammatical structure of speech and formation of coherent speech.
Detailed description
Neuroinflammation plays a central role in the pathogenesis of any damage to the central nervous system (CNS) profoundly affecting the ability of neural cells to survive and to regenerate. Macrophages play a key role in the regulation of neuroinflammation, but their role is ambiguous. In fact, macrophages can both induce neuronal and glial toxicity and promote tissue repair. The opposite effects of macrophages are largely due to their plasticity and functional heterogeneity. Thus, classical pro-inflammatory macrophages (M1) are tissue-destructive, while anti-inflammatory (M2) macrophages mediate tissue repair. In addition, M2 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]. The data indicate that M2, in contrast to pro-inflammatory M1, 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 high IL-10 level. M2 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.
Pilot clinical trials have demonstrated the safety and clinical efficacy of intrathecal administration of M2 in children with severe cerebral palsy [2, 3] and in nonacute stroke patients [4]. Moreover, intranasal delivery of M2 macrophage-derived soluble products reduces neuropsychological deficit in patients with cerebrovascular disease [5]. Given this data, the investigators expect that intranasal administration of the M2-BFs (Bioactive Factors) will reduce the severity of speech disorders in children, including improving speech understanding, sensorimotor speech level, word formation skills, as well as the formation of the grammatical structure of speech and coherent speech. Of note, intranasal administration of M2 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 M2-BFs | Experimental | Biological: Bioactive Factors, Produced by M2 Type Macrophages (M2-BFs).Intranasally-Administered Bioactive Factors, Produced by M2 Type Macrophages (M2-BFs). M2 were generated in vitro from peripheral blood of a parent during 7 days. Cell-free culture medium, containing M2-BFs, was collected, and aliquots of 2 mL/vial were cryopreserved. 30 children with speech disorders will receive their first doses (n=2-3) of 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. |
Who may qualify
- Ages
- 3 to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (5 listed)
- Age 3-18
- Speech disorders verified by speech therapist and neurologist
- Adequate hearing/vision to follow conversation
- Russian speaker
- A written informed consent of the parents/close relatives
Key exclusion criteria (4 listed)
- Acute infectious disease (bacterial, fungal, or viral)
- Seizures
- Intolerance to gentamicin and/or multiple drug allergies
- Participation in other clinical trials
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 |
|---|---|---|
| Bioactive Factors, Produced by M2 Type Macrophages (M2-BFs).Intranasal delivery of M2-BFs is performed with the aerosol inhaler device (nebulizer), 2.0 mL once a day up to 30 days. | Biological | Intranasal M2-BFs |
Primary outcome
Change in the severity of speech disorders according to Speech Assessment Scale (SAS)
Time frame: Baseline and 6 months after treatment
Speech Assessment Scale (SAS) is used to assess language development in children in six functional domains: Speech Comprehension; Sensomotor speech level; Grammatical structure of speech and inflection; Vocabulary and vocabulary skills; Connected speech; Gross and fine motor skills. Max total score:160 points (units of scale). Clinical improvement is manifested in an enhancement in the SAS score.
1 secondary outcome
The number of patients with adverse events
Time frame: up to 6 months after treatment
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 May 2022.
- 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.
- BackgroundChernykh ER, Shevela EYa, Kafanova MYu, Sakhno LV, Polovnikov EV, Ostanin AA. Monocyte-derived macrophages for treatment of cerebral palsy: a study of 57 cases. J Neurorestoratology. 2018; 6: 41-47. doi.org/10.2147/JN.S158843
- 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.
- BackgroundShevela E, Davydova M, Starostina N, Yankovskaya A, Ostanin A, Chernykh E. Intranasal delivery of M2 macrophage-derived soluble products reduces neuropsychological deficit in patients with cerebrovascular disease: a pilot study. J Neurorestoratology. 2019; 7: 89-100. doi:10.26599/JNR.2019.9040010
- Shevela E.Y., et al. Therapeutic effect of soluble factors of M2 phenotype macrophages in children with language impairments. Medical Immunology (Russia). 2021;23(5):1137-1150. (In Russ.) https://doi.org/10.15789/1563-0625-TEO-2224Link provided by the sponsor.
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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 Bioactive Factors, Produced by M2 Type Macrophages (M2-BFs). in people with Language Delay and Language; Developmental Disorder, Expressive, 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 5 inclusion and 4 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 2 May 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 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Change in the severity of speech disorders according to Speech Assessment Scale (SAS) (time frame: Baseline and 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 NCT04689282, 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 2 May 2022.