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Potential Use of Autologous and Allogeneic Mesenchymal Stem Cells in Patients With Multiple System Atrophy

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ClinicalTrials.gov Identifier: NCT04876326
Recruitment Status : Recruiting
First Posted : May 6, 2021
Last Update Posted : May 6, 2021
Sponsor:
Information provided by (Responsible Party):
Ismail Hadisoebroto Dilogo, Indonesia University

Brief Summary:

The prevalence of Multiple System Atrophy (MSA) is reported to be between 3.4 - 4.9 cases per 100,000 population. The estimated average incidence is 0.6 - 0.7 cases per 100,000 people per year. Many patients are not diagnosed properly during their lifetime because of the difficulty in differentiating MSA from other disorders. Approximately 29 - 33% of patients with isolated late onset cerebellar ataxia and 8 - 10% of patients with parkinsonism will develop MSA.

There are currently no therapies that can cure or stop the progression of the disease. The current pharmacological therapy is only to relieve symptoms. Mesenchymal stem cells (MSC) are considered an efficient source of cells for therapy, because they can be safely harvested and transplanted to donors or patients, have low immunogenicity, and have broad therapeutic potential. Results from preliminary preclinical and clinical trials indicate the potential of MSC-based treatment in meeting several key aspects of neurodegeneration. Stem cell-based therapy for neurodegenerative diseases aims to stop clinical damage by regenerating and by providing local support for damaged tissue, in addition after transplantation, MSCs have been shown to be capable of penetrating the lesion area and thus have great potential use as a means of administering therapeutic agents.

The subjects of this study were patients who experienced possible MSA based on the consensus clinical criteria for MSA. There will be three treatment groups with a total sample of 5 subjects each.

Group 1 will receives MSC-Adipose Autologous with doses 2x50 million cells intratechally.

Group 2 will receives MSC-Umbilical Cord Allogeneic with doses 2x 50 million cells intratechally.

Group 3 will receives MSC-Umbilical Cord Allogeneic with doses 2x50 million cells intratechally and 2x10cc secretome MSC from Adipose Intravenously.

Clinical improvement will be evaluated using the UMSARS scale, PET-Scans, MRI, DaTScan, IGF-1, BDNF, Sympathetic skin respons (SSR), EMG, Composite Autonomic Severity Score (CASS), High definition-Optical coherence tomography (HD-OCT), ERG, VEP, Log MAR chart, Ishihara test and side adverse effect on MSC.

This study is divided into six timeframes : Before an implantation, First Month after second implantation, Third month after secondary implantation, Sixth month after second implantation, Ninth month after second implantation and Twelve month after second implantation. The differences between the test variables are then used as an indicator to assess clinical improvement within the subjects.


Condition or disease Intervention/treatment Phase
Multiple System Atrophy Parkinsonism Multiple System Atrophy, Parkinson Variant Biological: Autologous Adipose Mesenchymal Stem Cell Implantation Biological: Allogeneic Umbilical Cord Mesenchymal Stem Cell Implantation Biological: Allogeneic Umbilical Cord Mesenchymal Stem Cell and Adipose Secretome Implantation Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: Potential Use of Autologous and Allogeneic Mesenchymal Stem Cells in Patients With Multiple System Atrophy
Actual Study Start Date : October 5, 2020
Estimated Primary Completion Date : October 5, 2021
Estimated Study Completion Date : October 5, 2021


Arm Intervention/treatment
Active Comparator: Autologous Adipose MSC Group
This group will receive the implantation of autologous mesenchymal stem cell origin of adipose tissue with a dose of 2 x 50 million cells given with a distance of 1 month
Biological: Autologous Adipose Mesenchymal Stem Cell Implantation

Before taking adipose tissue, each subject was screened including HbSAg, Anti HbS, Anti HCV, HIC, MCV and syphilis tests.

Adipose tissue was taken through 5 grams of subcutaneous fat biopsy from the abdomen of each subject and put into a transport medium and then sent to the RSCM-FKUI cGMP IPT Stem Cells Laboratory for immediate isolation of mesenchymal stem cells.

MSC that has been isolated will be cultured using the appropriate medium until it reaches the desired passage and the number of cells.

The viability and proliferation ability of cultured cells were evaluated, then characterization of cell antigen expression was carried out using flow cytometry to confirm the success of MSC culture.

The MSC to be injected into the subject will be prepared in 2cc physiological NaCl transport medium just before implantation.

The adipose secretion used is prepared in whole form as much as 10cc in a 10cc syringe.


Active Comparator: Allogeneic Umbilical Cord MSC Group
This group will receive intrathecal implantation of allogeneic mesenchymal stem cells from the umbilical cord with a dose of 2 x 50 million cells given a distance of 1 month.
Biological: Allogeneic Umbilical Cord Mesenchymal Stem Cell Implantation

Before taking the umbilical cord tissue, a pregnant woman's donor was screened including HbSAg, Anti HbS, Anti HCV, HIC, MCV and syphilis tests.

Immediately after delivery, the umbilical cord was collected and stored in a sterile specimen plate containing 0.9% NaCl at 4⁰C.

The umbilical cord is transported to the GMP standard culture laboratory at the UPT TK Stem Cells RSCM-FKUI for isolation process of mesenchymal stem cells. Sample processing was carried out within 8 hours of delivery to maintain cell viability.

MSC that has been isolated will be cultured using the appropriate medium until it reaches the desired passage and the number of cells.

The viability and proliferation ability of cultured cells were evaluated, then characterization of cell antigen expression was carried out using flow cytometry to confirm the success of MSC culture.

The MSC to be injected into the subject will be prepared in a suitable transport medium just prior to implantation.


Active Comparator: Allogeneic Umbilical Cord MSC and Adipose Secretome Group
This group will receive intrathecal implantation of allogeneic mesenchymal stem cells from the umbilical cord as much as 2 x 50 million followed by 2 x 10cc mesenchymal stem cell secretions from adipose tissue intravenously given at a distance of 1 month.
Biological: Allogeneic Umbilical Cord Mesenchymal Stem Cell and Adipose Secretome Implantation

Before taking adipose and umbilical cord tissue, each subject was screened. -For Adipose tissue : The adipose secretion used is prepared in whole form as much as 10cc in a 10cc syringe.

-Uc-MSC : Immediately after delivery, the umbilical cord was collected and stored in a sterile specimen plate containing 0.9% NaCl at 4⁰C.

The umbilical cord is transported to the GMP standard culture laboratory to have isolation process of mesenchymal stem cells. Sample processing was carried out within 8 hours of delivery to maintain cell viability.

Later it will be cultured using the appropriate medium until it reaches the desired passage and the number of cells.The viability and proliferation ability of cultured cells were evaluated, then characterization of cell antigen expression was carried out using flow cytometry to confirm the success of MSC culture.





Primary Outcome Measures :
  1. Changes of Clinical Evaluation from Baseline to 1,3,6,9 and 12 months after second implantation [ Time Frame: Pre-implantation, 1st Month, 3rd Months, 6th Months , 9th, 12th Months After Second Implantation ]
    Subjects will be evaluated by Neurological test

  2. Changes of Clinical Evaluation from Baseline to 1,3,6,9 and 12 months after second implantation [ Time Frame: Pre-implantation, 1st Month, 3rd Months, 6th Months , 9th, 12th Months After Second Implantation ]
    Subjects will be evaluated by UMSARS(Unified Multiple System Atrophy Rating Scale)

  3. Changes of structures improvement of the eyes from Baseline to 1,3,6,9 and 12 months after second implantation [ Time Frame: Pre-implantation, 1st Month, 3rd Months, 6th Months , 9th, 12th Months After Second Implantation ]
    an increase in the thickness of the Retinal Nerve Fiber Layer(RNFL) checked from the High Definition-Optical Coherence Tomography examination(HD-OCT)

  4. Changes of structures improvement of the eyes from Baseline to 1,3,6,9 and 12 months after second implantation [ Time Frame: Pre-implantation, 1st Month, 3rd Months, 6th Months , 9th, 12th Months After Second Implantation ]
    an increase in the Ganglion Cell Complex (GCC) checked from the High Definition-Optical Coherence Tomography examination(HD-OCT)

  5. Changes of the eyesight from Baseline to 1,3,6,9 and 12 months after second implantation [ Time Frame: Pre-implantation, 1st Month, 3rd Months, 6th Months , 9th, 12th Months After Second Implantation ]
    improvement of eyesight will be checked using LogMar Test

  6. Changes of the eyesight from Baseline to 1,3,6,9 and 12 months after second implantation [ Time Frame: Pre-implantation, 1st Month, 3rd Months, 6th Months , 9th, 12th Months After Second Implantation ]
    improvement of eyesight will be checked using Ishihara test

  7. Changes of the eyesight from Baseline to 1,3,6,9 and 12 months after second implantation [ Time Frame: Pre-implantation, 1st Month, 3rd Months, 6th Months , 9th, 12th Months After Second Implantation ]
    improvement of eyesight will be checked using VEP (Visual Evoked Potential)

  8. Changes of the eyesight from Baseline to 1,3,6,9 and 12 months after second implantation [ Time Frame: Pre-implantation, 1st Month, 3rd Months, 6th Months , 9th, 12th Months After Second Implantation ]
    improvement of eyesight will be checked using ERG (Electroretinogram)

  9. Imaging Evaluation from Baseline to 1,3,6,9 and 12 months after second implantation [ Time Frame: Pre-implantation, 1st Month, 3rd Months, 6th Months , 9th, 12th Months After Second Implantation ]
    The Brain will be checked to see Changes of MRI to see increased FDG Uptake

  10. Imaging Evaluation from Baseline to 1,3,6,9 and 12 months after second implantation [ Time Frame: Pre-implantation, 1st Month, 3rd Months, 6th Months , 9th, 12th Months After Second Implantation ]
    The Brain will be checked to see Changes of FGD-PET SCAN to see increased FDG Uptake

  11. Imaging Evaluation from Baseline to 1,3,6,9 and 12 months after second implantation [ Time Frame: Pre-implantation, 1st Month, 3rd Months, 6th Months , 9th, 12th Months After Second Implantation ]
    The Brain will be checked to see Changes of DaTScan to see increased FDG Uptake



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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients developed MSA based on clinical examination and consensus MSA criteria.
  • Patients diagnosed with MSA for less than 4 years.
  • Patients with an anticipated survival of at least 3 years in the opinion of the examiner.
  • Patients with MOCa and Mini Mental State Examination (MMSE) values of more than 24.
  • For Adipose Autologous-MSC group subjects were not experiencing active infection, which was confirmed by screening for HbSAg, Anti HCV, Syphilis, HIV, CMV, Rubella, and Toxoplasma.
  • Subjects are willing to participate in research and fill out an informed consent form.
  • Do not have autoimmune disorder, or undergoes management disorders and / or other diseases related to MSA
  • Subjects are willing to participate in research and fill out an informed consent form.

Exclusion Criteria:

  • Suffer from systemic autoimmune diseases (systemetic lupus erythomatosus, Addison's disease, Crohn's disease, arthritis management), immunodeficiency (SIDA), or blood clotting disorders or management of malignant diseases (diseases associated with MSA)
  • Undergo immunosuppressive therapy, anticoagulants or corticosteroids.
  • Patients with malignant neoplasms and close family history of neoplasms.
  • already had history of spinal surgery, have paralysis or have spinal diseases.
  • Patients with a history of electroconvulsive therapy.
  • Patients with a history of brain surgery for Parkinson's disease.
  • Patients with systemic or local infections located close to the injection site.
  • Undergo immunosuppressive therapy, anticoagulants or corticosteroids.
  • The patient was not willing to take part in the study and did not fill out informed consent.

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 ClinicalTrials.gov identifier (NCT number): NCT04876326


Locations
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Indonesia
Cipto Mangunkusumo General Hospital Recruiting
Jakarta Pusat, DKI Jakarta, Indonesia
Contact: Ismail H Dilogo, MD, PhD    +62211500135    ismailortho@gmail.com   
Principal Investigator: Ismail H Dilogo, MD, PhD         
Sub-Investigator: Teguh AS Ranakusuma, MD,PhD         
Sub-Investigator: Salim Haris, MD,PhD         
Sub-Investigator: Yetty Ramli, MD,PhD         
Sub-Investigator: Ahmad Y Safri, MD         
Sub-Investigator: Rahyussalim Rahyussalim, MD, PhD         
Sub-Investigator: Isabella K Liem, MD, PhD         
Sub-Investigator: Radiana D Antarianto, MD, PhD         
Sub-Investigator: Ira Mistivani, MD         
Sub-Investigator: Amanda Tiksnadi, MD         
Sub-Investigator: Winnugroho Wiratman, MD         
Sub-Investigator: Dyah Tunjungsari, MD         
Sub-Investigator: Reyhan E Yunus, MD         
Sub-Investigator: Alvita D Siswoyo, MD         
Sub-Investigator: Andi A Victor, MD         
Sub-Investigator: Syntia Nusanti, MD         
Sub-Investigator: Anggun R Yudhanta, MD         
Sub-Investigator: Jeanne A Pawitan, MD         
Sub-Investigator: Tri Kurniawati, SSi         
Sponsors and Collaborators
Indonesia University
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Responsible Party: Ismail Hadisoebroto Dilogo, Principal Investigator, Indonesia University
ClinicalTrials.gov Identifier: NCT04876326    
Other Study ID Numbers: TGHISMMSCMSA
First Posted: May 6, 2021    Key Record Dates
Last Update Posted: May 6, 2021
Last Verified: May 2021

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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 Ismail Hadisoebroto Dilogo, Indonesia University:
Multiple System Atrophy, Parkinson Variant
Mesenchymal Stem Cell
Parkinsonism
UMSARS
MRI
FGD-PET SCAN
DaTScan
SSR, RR-Interval
Composite Autonomic Severity Score
ILG-1, BDNF
ERG (Electroretinogram)
VEP (Visual Evoked Potential)
HD-OCT (High Definition-optical coherence tomography)
Additional relevant MeSH terms:
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Multiple System Atrophy
Shy-Drager Syndrome
Parkinsonian Disorders
Atrophy
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Synucleinopathies
Neurodegenerative Diseases
Pathological Conditions, Anatomical
Primary Dysautonomias
Autonomic Nervous System Diseases
Hypotension
Vascular Diseases
Cardiovascular Diseases