Clinical trial NCT04744051: ATCell™ Expanded Autologous, Adipose-Derived Mesenchymal Stem Cells Deployed Via Intravenous Infusion
Official title: ATCell™ Expanded Autologous, Adipose-Derived Mesenchymal Stem Cells Deployed Via Intravenous Infusion for the Treatment of Post Concussion Syndrome (PCS) in Retired Military and Athletes
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: Post-Concussion Syndrome
Keywords: Concussion
Adipose Derived Stem Cell
Mesenchymal Stem Cell
Adult Stem Cell
Traumatic Brain Injury
Athletes
Military
Chronic Concussion Syndrome
Post Concussion Syndrome
Lead sponsor: American CryoStem Corporation
Sponsor class: INDUSTRY
First posted: 2021-02-08
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The proposed study is a single-site, double-blinded, placebo-controlled study involving a single administration of either individual, autologous ATCell™ lines suspended in 5% dextrose lactated Ringer's solution or a vehicle (5% dextrose lactated Ringer's solution) not containing cells. Each ATCell™ cell line will be created from cells grown from the stromal vascular fraction (SVF) of a participant's own adipose tissue collected by liposuction, and each treated participant will only receive their own cells.
Primary purpose: TREATMENT

Brief summary: This is a Phase 1 Clinical Safety Study intended to provide preliminary assessments of the safety, tolerability, and clinical alleviation of symptoms associated with Post Concussion Syndrome (PCS), also known as Chronic Concussive Syndrome (CCS).

Detailed description: The proposed study is a single-site, double-blinded, placebo-controlled study involving a single administration of either individual, autologous ATCell™ lines suspended in 5% dextrose lactated Ringer's solution or a vehicle (5% dextrose Lactated Ringer's solution) not containing cells. Each ATCell™ cell line will be created from cells grown from the stromal vascular fraction (SVF) of a participant's own adipose tissue collected by liposuction, and each treated participant will only receive their own cells.

Within the treated group, 3 dosing levels will be explored: 50 million cells, 150 million cells, or 300 million cells, and a Placebo group which will receive 5% dextrose lactated Ringer's solution free of cells. Participant follow-ups will take place 1 day following the tissue harvest procedure and, 1 day, 1 week, 1 month, 3 months, and 6 months following ATCell™ treatment. Comprehensive participant's evaluations involving data collection will take place 1, 3, and 6 months following treatment.

It has been proposed that in general, mild traumatic brain injuries (TBI) events need to be taken far more seriously, and that even mild TBI events can result in lasting negative consequences as evidenced by lower performances on neuropsychological assessments when compared with age-matched controls2. In fact, this condition may eventually lead to Alzheimer's Disease (AD) as well as Chronic Traumatic Encephalopathy (CTE), which, together may be termed the AD-like dementias3, further underscoring the need for effective clinical intervention. Currently, no effective treatments are available for this condition aside from treatment of the symptoms, although some more comprehensive treatments have been proposed.

Eligibility criteria: Inclusion Criteria:

1. Reviewed and personally signed and dated informed consent document indicating that the participant (or legally acceptable representative) has been informed of and understands all pertinent aspects of the study.
2. Confirmed Diagnosis of Chronic Concussive Syndrome/Post-Concussive Syndrome: At least three (3) of the following criteria must be met to confirm diagnosis:

   A. Persistent headaches

   B. Persistent dizziness

   C. Persistent fatigue

   D. Irritability, intolerance to stress, or unusual emotional reactions

   E. Lowered tolerance to noise and/or light

   F. Impaired memory or concentration

   G. Insomnia
3. Female participants of child bearing potential and at risk of pregnancy during the study must agree to use 2 highly effective methods of contraception throughout the study and for 112 days after the last study visit.
4. Female participant who are not of childbearing potential (i.e. must meet at least one (1) of the following criteria):

   i) Have undergone a documented hysterectomy and/or bilateral oophorectomy

   ii) Have medically confirmed ovarian failure

   iii) Achieved postmenopausal status defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or psychological cause and have a serum follicle stimulating hormone (FSH) level confirming the post menopausal state
5. Individuals who are willing and able to comply with lifestyle guidelines, scheduled visits, treatment plan, laboratory tests, and other study procedures through the end of the final study visit
6. Individuals Aged 18 to 65 at the time of screening and enrollment.

Exclusion Criteria:

1. Any cardiac pathologies or conditions which may risk the participant or interfere with the ability to interpret the results. Signs and symptoms of clinically significant cardiac disease including but not limited to:

   A. Ischemic cardiac disease (eq. unstable angina, myocardial infarction) in the 6 months prior to screening.

   B. New York Heart Association (NYHA) Class III or IV congestive heart failure or known left ventricular dysfunction with ejection fraction ≤ 35%, cardiomyopathy, myocarditis in the 6 months prior to screening.

   C. Resting tachycardia (heart rate ≥ 120) or resting bradycardia (heart ≤ 45) on ECG at screening.

   D. Any other cardiovascular illness that in the opinion of the Investigator would render an individual unable to participate in the study.

   E. Individuals with history of heart block.

   F. Individuals with a history of Atrial Fibrillation

   G. Individuals that have had stents implanted within one year of recruitment
2. History of transient ischemic attack in the 6 months prior to screening, diagnosis of stroke with residual deficits (eq. aphasia, substantial motor or sensory deficits) diagnosis of stroke with residual deficits (eq. aphasia, substantial motor or sensory deficits) that would preclude completion of required study activities
3. Resting, sitting blood pressure (BP) ≥ 160 mm Hg in systolic pressure or ≥ 100 mm Hg in diastolic pressure at screening. If a participant is found to have untreated significant hypertension at screening and antihypertensive treatment is initiated, assessment for study eligibility should be deferred until BP and antihypertensive medication have been stable for at least 1 month. For participants with previously diagnosed hypertension, antihypertensive medications must be stable for at least 1 month prior to screening
4. Participants who have evidence of orthostatic hypotension based upon replicate orthostatic blood pressure measurements. If orthostatic blood pressure change is not able to be determined (e.g., unable to establish a stable supine systolic and diastolic blood pressure) the participant is not eligible for the study
5. Individuals with a history of Deep Vein Thrombosis (DVT) or pulmonary embolism
6. Individuals with a history or family history of thrombophilia such as Factor V Leiden
7. Individuals that have had stents implanted within the past year
8. Individuals that are currently being treated with an anticoagulant medication
9. History, diagnosis, or signs and symptoms of clinically significant neurological disease, including but not limited to:

   A. Alzheimer's disease or other type of dementia

   B. Peripheral or autonomic neuropathy

   C. Multiple sclerosis

   D. Epilepsy or seizure disorder with history of seizure within the last 2 years

   E. Myopathy

   F. White matter disease
10. Individuals currently being treated with specific prescription immunomodulatory agents:

    A. Certolizumab (Cimzia™)

    B. Infliximab (REMICADE™)

    C. Etanercept (Enbrel™)

    D. Prednisone (Deltasone, Rayos, Prednisone Intensol)

    E. Prednisolone (Omnipred™)

    F. Dexamethasone (Ozurdex™)

    G. Any drug which the investigator believes would compromise the results or interfere with ATCell™ effectiveness
11. Participant with any active or chronic infection
12. Life-threading organ dysfunction
13. Planned surgical procedure during the duration of the study
14. Largely or wholly incapacitated (eq. individual bedridden or confined to wheelchair, permitting little or no self care)
15. Pregnant or actively breastfeeding females; females of childbearing potential who are unwilling or unable to use 2 highly effective methods of contraception as outlined in this protocol for the duration of the study, meaning 6 months after ATCell™ administration
16. Severe physical limitations or disabilities
17. Participants who are seropositive for Human Immunodeficiency Virus -1 (HIV1), Human Immunodeficiency Virus -2 (HIV2), Hepatitis B Surface Antigen and Hepatitis C, indicative of current infection
18. Participant unable to give written consent in accordance with institutional review board guidelines
19. Treatment with any immunosuppressive therapy within 3 months of evaluation
20. Current or recent treatment (within 3 months of evaluation) with an investigational drug and/or therapy (phase 1-4) within 90 days of screening
21. Individuals with a concurrent diagnosis of malignant neoplasm (cancer)
22. History of cancer within 5 years prior to screening, except for cutaneous basal cell or squamous cell cancer resolved by excision
23. Individuals with inadequate subcutaneous tissue to allow for appropriate lipoaspirate collection
24. Other severe or chronic medical psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make this individual inappropriate for entry into this study
25. Individuals with immunodeficiencies or severe autoimmune disease
26. Individuals allergic to local anesthetics
27. Individuals with any contraindication to liposuction, in the investigator's opinion
28. History of coagulation disorders that would put them at risk
29. Individuals, in the opinion of the investigator, unable to comply with the requirements of the study protocol or is unsuitable for the study for any reason
30. The individual is involved in an active civil, criminal or workers compensation case other than the NFL class action
31. Individuals unable or unwilling to return for the required follow-up evaluations
32. Presence of drugs of abuse (including cannabis and prescription medications without valid prescription), or illegal drugs in the urine toxicology test obtained at screening
33. History of known alcohol, analgesic or drug abuse within 2 years of screening
34. Individuals who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or who are employees directly involved in the conduct of the study

Primary outcomes:
measure: Health Status using the 36 item Short Form Health Survey (SF-36)
timeFrame: Baseline, 1 month and 6 months post treatment
measure: Assessment of Visual Attention and Task Switching
timeFrame: Baseline, 1 month and 6 months post treatment
measure: Assessment of Contextual Verbal Learning
timeFrame: Baseline, 1 month post treatment and 6 months post treatment
measure: Assessment of Verbal Fluency
timeFrame: Baseline, 1 month post treatment and 6 months post treatment
measure: Assessment of Attention and Executive functions
timeFrame: Baseline, 1 month post treatment and 6 months post treatment
measure: Assessment of Unstructured Verbal Learning and Memory
timeFrame: Baseline, 1 month post treatment and 6 months post treatment
measure: Assessment of Visuospatial Learning and Memory
timeFrame: Baseline, 1 month post treatment and 6 months post treatment
measure: Assessment of Symptoms of Anxiety over Time
timeFrame: Baseline, 1 month post treatment and 6 months post treatment
measure: Assessment of Pain
timeFrame: Baseline, 1 month post treatment and 6 months post treatment
measure: Assessment of Sleep Quality
timeFrame: Baseline, 1 month post treatment and 6 months post treatment
measure: Assessment of Treatment by Participant
timeFrame: Baseline, 1 month post treatment and 6 months post treatment
measure: Assessment of Depression by Participant
timeFrame: Baseline, 1 month post treatment and 6 months post treatment
Secondary outcomes:
Other outcomes:
Locations:
city: La Mesa
country: United States
facility: BioSolutions Clinical Research Center
state: California
Study officials:
affiliation: Biosolutions Clinical Research Center
name: Peter B Hanson, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Stein MB, Ursano RJ, Campbell-Sills L, Colpe LJ, Fullerton CS, Heeringa SG, Nock MK, Sampson NA, Schoenbaum M, Sun X, Jain S, Kessler RC. Prognostic Indicators of Persistent Post-Concussive Symptoms after Deployment-Related Mild Traumatic Brain Injury: A Prospective Longitudinal Study in U.S. Army Soldiers. J Neurotrauma. 2016 Dec 1;33(23):2125-2132. doi: 10.1089/neu.2015.4320. Epub 2016 Apr 8.
citation: Sterr A, Herron KA, Hayward C, Montaldi D. Are mild head injuries as mild as we think? Neurobehavioral concomitants of chronic post-concussion syndrome. BMC Neurol. 2006 Feb 6;6:7. doi: 10.1186/1471-2377-6-7.
citation: Ramos-Cejudo J, Wisniewski T, Marmar C, Zetterberg H, Blennow K, de Leon MJ, Fossati S. Traumatic Brain Injury and Alzheimer's Disease: The Cerebrovascular Link. EBioMedicine. 2018 Feb;28:21-30. doi: 10.1016/j.ebiom.2018.01.021. Epub 2018 Jan 31.
citation: McKee AC, Robinson ME. Military-related traumatic brain injury and neurodegeneration. Alzheimers Dement. 2014 Jun;10(3 Suppl):S242-53. doi: 10.1016/j.jalz.2014.04.003.
citation: Thompson M, Mei SHJ, Wolfe D, Champagne J, Fergusson D, Stewart DJ, Sullivan KJ, Doxtator E, Lalu M, English SW, Granton J, Hutton B, Marshall J, Maybee A, Walley KR, Santos CD, Winston B, McIntyre L. Cell therapy with intravascular administration of mesenchymal stromal cells continues to appear safe: An updated systematic review and meta-analysis. EClinicalMedicine. 2020 Jan 17;19:100249. doi: 10.1016/j.eclinm.2019.100249. eCollection 2020 Feb.
citation: Toyserkani NM, Jorgensen MG, Tabatabaeifar S, Jensen CH, Sheikh SP, Sorensen JA. Concise Review: A Safety Assessment of Adipose-Derived Cell Therapy in Clinical Trials: A Systematic Review of Reported Adverse Events. Stem Cells Transl Med. 2017 Sep;6(9):1786-1794. doi: 10.1002/sctm.17-0031. Epub 2017 Jul 19.