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Intranasal Inhalations of M2 Macrophage Soluble Factors in Children With Developmental Speech Disorders

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04689282
Recruitment Status : Recruiting
First Posted : December 30, 2020
Last Update Posted : December 30, 2020
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 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.

Condition or disease Intervention/treatment Phase
Language Delay Language; Developmental Disorder, Expressive Language; Developmental Disorder, Receptive Autism Spectrum Disorder Attention Deficit-Hyperactivity Disorder Speech Disorders in Children Biological: Bioactive Factors, Produced by M2 Type Macrophages (M2-BFs). Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated 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 M2 Type Macrophages in Children With Developmental Speech Disorders
Actual Study Start Date : February 1, 2020
Estimated Primary Completion Date : December 1, 2021
Estimated Study Completion Date : July 1, 2022

Arm Intervention/treatment
Experimental: Intranasal 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.

Biological: 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.

Primary Outcome Measures :
  1. 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.

Secondary Outcome Measures :
  1. The number of patients with adverse events [ Time Frame: up to 6 months after treatment ]
    Occurrence of adverse events including allergic, toxic, inflammatory reactions; neurological worsening; seizures

Information from the National Library of Medicine

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Ages Eligible for Study:   3 Years to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • Acute infectious disease (bacterial, fungal, or viral)
  • Seizures
  • 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 identifier (NCT number): NCT04689282

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Contact: Valentina G Degtyareva, PhD +7 (383) 211-40-05
Contact: Ekaterina Y Shevela, MD, PhD +7 (383) 228-21-01

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Russian Federation
Institute of Fundamental and Clinical Immunology Recruiting
Novosibirsk, Russian Federation, 630099
Contact: Elena R Chernykh, MD, PhD    +7 (383) 236-03-29   
Contact: Alexander A Ostanin, MD, PhD    +7 (383) 236-03-29   
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
Chernykh 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.
Shevela 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

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Responsible Party: Alexander A Ostanin, Head of Clinical Department, Russian Academy of Medical Sciences Identifier: NCT04689282    
Other Study ID Numbers: IFCI-23/06/2017
First Posted: December 30, 2020    Key Record Dates
Last Update Posted: December 30, 2020
Last Verified: December 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Alexander A Ostanin, Russian Academy of Medical Sciences:
M2 type macrophages
Intranasal administration
Speech disorders
Additional relevant MeSH terms:
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Speech Disorders
Language Development Disorders
Attention Deficit Disorder with Hyperactivity
Autism Spectrum Disorder
Developmental Disabilities
Pathologic Processes
Attention Deficit and Disruptive Behavior Disorders
Neurodevelopmental Disorders
Mental Disorders
Neurologic Manifestations
Nervous System Diseases
Child Development Disorders, Pervasive
Language Disorders
Communication Disorders
Neurobehavioral Manifestations