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Clinical Efficacy of Autologous Mesenchymal Bone Marrow Stem Cells in Active & Progressive Multiple Sclerosis

Primary Purpose

Multiple Sclerosis (MS)

Status
Completed
Phase
Phase 2
Locations
Israel
Study Type
Interventional
Intervention
Mesenchymal stem cells
Sponsored by
Dimitrios Karussis
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Multiple Sclerosis (MS) focused on measuring Multiple Sclerosis (MS), Stem Cells

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Consenting patients fulfilling the Poser's clinical criteria for definite MS
  2. Age: 18-65, males and females
  3. Duration of disease: >3 years
  4. Progressive form of MS: PPMS, SPMS (with/without relapses)
  5. EDSS score of 3.5 - 6.5
  6. Failure to currently available, registered - first and second line immunomodulatory treatments (at least one).
  7. Evidence for new activity of MS during the 3 months before the injection of MSC.

Exclusion Criteria:

  1. Patients who were treated with cytotoxic medications during the last 3 months prior to the inclusion.
  2. Patients suffering from significant cardiac, renal or hepatic failure or any other disease that may risk the patient or interfere with the ability to interpret the results
  3. Patients with active infections
  4. Patients with severe cognitive decline or inability to understand and sign the informed consent
  5. Patients who received any cellular treatment in the past

Sites / Locations

  • Hadassah Medical Organization

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Placebo Comparator

Arm Label

IT- Treated

IV - Treated

Placebo

Arm Description

Injection to IT (Group 1). After 6 months, 8 patients (group 1A) will be treated with MSC once again in IT, and 8 additional patients (group 1B) will receive a placebo.

Injection to IV (Group 2). After 6 months, 8 patients (group 2A) will be treated with MSC once again in IV, and 8 additional patients (group 2B) will receive a placebo.

Placebo at the first injection (group 3). After 6 months, 8 patients (group 3A) will be treated with MSC in IT, and 8 additional patients (group 3B) will be treated with MSC in IV.

Outcomes

Primary Outcome Measures

Safety Assessment
The proportions of the patients in the three treatment-groups (MSC-IV, MSC-IT and placebo) who experienced any adverse event.
Neurological efficacy
The proportions of the patients with treatment failure (increase of the EDSS by 1 point for patients with baseline values of 5.0 or less and of 0.5 degree for baseline EDSS of more than 5.0), confirmed by two consecutive evaluations, in the three treatment-groups.

Secondary Outcome Measures

EDSS score
Change from baseline to 6 months visit post each treatment cycle in EDSS following treatment with intravenous or intrathecal MSC infusion, vs. placebo treatment in MS patients at 6 months post treatment. [A decrease in EDSS indicates clinical improvement].
Ambulation score
Change from baseline to 6 months visit post each treatment cycle in ambulation score following treatment with intravenous or intrathecal MSC infusion, vs. placebo treatment in MS patients at 6 months post treatment. [A decrease in ambulation score indicates clinical improvement].
Functional scores
Change from baseline to 6 months visit post each treatment cycle in the sum of all functional scores (from the EDSS scoring) following treatment with intravenous or intrathecal MSC infusion, vs. placebo treatment in MS patients at 6 months post treatment. [A decrease in the sum of functional scores indicates clinical improvement].
Single injection vs. repeated MSCs injection
Change from baseline to final 12-month visit, in EDSS following treatment of a single injection of MSCs vs. repeated MSCs injections treatment. [A decrease in EDSS indicates clinical improvement]. *similar comparison will be performed for the ambulation score and the sum of all functional systems' scores
Relapse rate
Annualized MS-Relapse rate during the 6 months of each treatment cycle, in the three treatment groups.
T2-weighted flair lesions load in MRI
The annualized rate of change in the total lesions load of the T2-weighted MRI scans during the 6 months of each cycle of treatment versus the rate of change in the run-in period (before the treatment). [An increase in the volume of lesions indicates progression of the disease].
Total brain volume in MRI
The annualized rate of change in total brain volume in MRI scans during the 6 months of each cycle of treatment versus the rate of change in the run-in period (before the treatment). [A decrease in the brain volume indicates progression of the disease].
Gadolinium enhancing lesions in MRI
The mean annualized number of gadolinium-enhancing lesions during the 6 months of each treatment cycle, in the three treatment groups. [The appearance of gadolinium-enhancing lesions in MRI indicates activity of the disease].
Functional MRI
The annualized rate of change in the z-scores of the motor networks in resting functional MRI during the 6 months of each cycle of treatment versus the rate of change in the run-in period (before the treatment). [An increase in the z-score indicates functional improvement]. * similar measurements will apply for the pyramidal and visual networks
25-feet timed walking
The mean time to walk 25-feet during the 6 months in each treatment cycle vs the mean time during the run-in pre-treatment period. [A decrease in the value of timed walking indicates clinical improvement].
9-hole peg test
The mean time to perform the 9-hole peg test of hands dexterity during the 6 months in each treatment cycle vs the mean time during the run-in pre-treatment period. [A decrease in the value of timed walking indicates clinical improvement].
Paced Auditory Serial Addition Test (PASAT)
The score given in this neuropsychological test reflects the assess capacity and rate of information processing and sustained and divided attention. This perform during the 6 months in each treatment cycle vs the mean time during the run-in pre-treatment period. [An increase in z score indicates clinical improvement]
Cognitive function: Controlled Oral Word Association Test (COWAT)
The annualized rate of change in the z-scores of the COWAT cognitive test during the 6 months of each cycle of treatment versus the rate of change in the run-in period (before the treatment). [An increase in the z-score indicates functional improvement]. * similar measurements will apply for other cognitive tests (SDMT)
Optical coherence tomography (OCT)
Change from baseline to 6 months visit, post each treatment cycle retinal nerve fiber layer (RNFL) thickness in OCT, following treatment with intravenous or intrathecal MSC infusion, vs. placebo treatment in MS patients at 6 months post treatment. [An increase in RNFL thickness indicates clinical improvement]. * similar measurements will apply for Macula thickness
Immunology
Change from baseline to 6 months visit post each treatment cycle in the proportion of the lymphocytes expressing the CD4+CD25+ markers (T-regulatory cells) following treatment with intravenous or intrathecal MSC infusion, vs. placebo treatment at 6 months post treatment. [An increase in the proportion may indicate beneficial effects]. * similar measurements (for evaluation of safety of the treatment) will be performed for additional white blood cell subpopulations

Full Information

First Posted
May 20, 2014
Last Updated
July 30, 2019
Sponsor
Dimitrios Karussis
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1. Study Identification

Unique Protocol Identification Number
NCT02166021
Brief Title
Clinical Efficacy of Autologous Mesenchymal Bone Marrow Stem Cells in Active & Progressive Multiple Sclerosis
Official Title
Phase 2 Trial to Investigate the Clinical Efficacy & the Optimal Administration (Based on the Immunological, Clinical & Neuroradiological Effects) of Autologous Mesenchymal Bone Marrow Stem Cells in Active & Progressive Multiple Sclerosis
Study Type
Interventional

2. Study Status

Record Verification Date
July 2019
Overall Recruitment Status
Completed
Study Start Date
January 29, 2015 (Actual)
Primary Completion Date
June 15, 2018 (Actual)
Study Completion Date
December 24, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Dimitrios Karussis

4. Oversight

Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to evaluate the clinical efficacy and the optimal way of administration of autologous mesenchymal bone marrow stem cells (MSC) compering intravenous injection and intrathecal injection vs. placebo, in active-progressive Multiple Sclerosis patients.
Detailed Description
Mesenchymal stem cells (MSC) induce immune-modulatory and neurotrophic effects and were shown to have an acceptable safety profile for clinical applications. We aimed to evaluate the safety and efficacy of MSC transplantation in active progressive MS and investigate possible neuroprotective effects. Methods: This single-center double-blind crossover trial enrolled 48 patients with progressive MS (expanded disability status scale (EDSS) range: 3.5-6.5, mean: 5.6+/-0.8). Patients were randomised into three groups and treated intrathecally (IT) or intravenously (IV) with autologous MSCs (1x106/Kg) or placebo. At 6-months, treatment groups were crossed over and patients re-treated with either MSC or placebo. During the 2-months run-in period and the 12-months after treatment, participants were followed using EDSS, 25-foot timed walking, 9-hole peg test, neurocognitive tests, quantitative magnetic resonance imaging (MRI), functional MRI, optic coherence tomography (OCT), visual evoked potentials (VEP), and dynamic visual tests.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple Sclerosis (MS)
Keywords
Multiple Sclerosis (MS), Stem Cells

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Model Description
Patients were randomised into three groups and treated intrathecally (IT) or intravenously (IV) with autologous MSCs or placebo. At 6-months, treatment groups were crossed over and patients re-treated with either MSC or placebo
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
48 (Actual)

8. Arms, Groups, and Interventions

Arm Title
IT- Treated
Arm Type
Experimental
Arm Description
Injection to IT (Group 1). After 6 months, 8 patients (group 1A) will be treated with MSC once again in IT, and 8 additional patients (group 1B) will receive a placebo.
Arm Title
IV - Treated
Arm Type
Experimental
Arm Description
Injection to IV (Group 2). After 6 months, 8 patients (group 2A) will be treated with MSC once again in IV, and 8 additional patients (group 2B) will receive a placebo.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo at the first injection (group 3). After 6 months, 8 patients (group 3A) will be treated with MSC in IT, and 8 additional patients (group 3B) will be treated with MSC in IV.
Intervention Type
Biological
Intervention Name(s)
Mesenchymal stem cells
Other Intervention Name(s)
Autologous MSC
Intervention Description
A culture of purified MSCs was prepared under aseptic conditions, and cultured for 4 weeks, until they reached confluency, and were then harvested. After sterility was confirmed, the cells resuspended in normal saline at a concentration of 10 × 106/mL to 15 × 106/mL.
Primary Outcome Measure Information:
Title
Safety Assessment
Description
The proportions of the patients in the three treatment-groups (MSC-IV, MSC-IT and placebo) who experienced any adverse event.
Time Frame
6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group
Title
Neurological efficacy
Description
The proportions of the patients with treatment failure (increase of the EDSS by 1 point for patients with baseline values of 5.0 or less and of 0.5 degree for baseline EDSS of more than 5.0), confirmed by two consecutive evaluations, in the three treatment-groups.
Time Frame
6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group
Secondary Outcome Measure Information:
Title
EDSS score
Description
Change from baseline to 6 months visit post each treatment cycle in EDSS following treatment with intravenous or intrathecal MSC infusion, vs. placebo treatment in MS patients at 6 months post treatment. [A decrease in EDSS indicates clinical improvement].
Time Frame
6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group
Title
Ambulation score
Description
Change from baseline to 6 months visit post each treatment cycle in ambulation score following treatment with intravenous or intrathecal MSC infusion, vs. placebo treatment in MS patients at 6 months post treatment. [A decrease in ambulation score indicates clinical improvement].
Time Frame
6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group
Title
Functional scores
Description
Change from baseline to 6 months visit post each treatment cycle in the sum of all functional scores (from the EDSS scoring) following treatment with intravenous or intrathecal MSC infusion, vs. placebo treatment in MS patients at 6 months post treatment. [A decrease in the sum of functional scores indicates clinical improvement].
Time Frame
6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group
Title
Single injection vs. repeated MSCs injection
Description
Change from baseline to final 12-month visit, in EDSS following treatment of a single injection of MSCs vs. repeated MSCs injections treatment. [A decrease in EDSS indicates clinical improvement]. *similar comparison will be performed for the ambulation score and the sum of all functional systems' scores
Time Frame
12 months: ie the total duration of the trial
Title
Relapse rate
Description
Annualized MS-Relapse rate during the 6 months of each treatment cycle, in the three treatment groups.
Time Frame
12 months: ie the total duration of the trial
Title
T2-weighted flair lesions load in MRI
Description
The annualized rate of change in the total lesions load of the T2-weighted MRI scans during the 6 months of each cycle of treatment versus the rate of change in the run-in period (before the treatment). [An increase in the volume of lesions indicates progression of the disease].
Time Frame
6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group
Title
Total brain volume in MRI
Description
The annualized rate of change in total brain volume in MRI scans during the 6 months of each cycle of treatment versus the rate of change in the run-in period (before the treatment). [A decrease in the brain volume indicates progression of the disease].
Time Frame
6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group
Title
Gadolinium enhancing lesions in MRI
Description
The mean annualized number of gadolinium-enhancing lesions during the 6 months of each treatment cycle, in the three treatment groups. [The appearance of gadolinium-enhancing lesions in MRI indicates activity of the disease].
Time Frame
6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group
Title
Functional MRI
Description
The annualized rate of change in the z-scores of the motor networks in resting functional MRI during the 6 months of each cycle of treatment versus the rate of change in the run-in period (before the treatment). [An increase in the z-score indicates functional improvement]. * similar measurements will apply for the pyramidal and visual networks
Time Frame
6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group
Title
25-feet timed walking
Description
The mean time to walk 25-feet during the 6 months in each treatment cycle vs the mean time during the run-in pre-treatment period. [A decrease in the value of timed walking indicates clinical improvement].
Time Frame
6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group
Title
9-hole peg test
Description
The mean time to perform the 9-hole peg test of hands dexterity during the 6 months in each treatment cycle vs the mean time during the run-in pre-treatment period. [A decrease in the value of timed walking indicates clinical improvement].
Time Frame
6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group
Title
Paced Auditory Serial Addition Test (PASAT)
Description
The score given in this neuropsychological test reflects the assess capacity and rate of information processing and sustained and divided attention. This perform during the 6 months in each treatment cycle vs the mean time during the run-in pre-treatment period. [An increase in z score indicates clinical improvement]
Time Frame
6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group
Title
Cognitive function: Controlled Oral Word Association Test (COWAT)
Description
The annualized rate of change in the z-scores of the COWAT cognitive test during the 6 months of each cycle of treatment versus the rate of change in the run-in period (before the treatment). [An increase in the z-score indicates functional improvement]. * similar measurements will apply for other cognitive tests (SDMT)
Time Frame
6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group
Title
Optical coherence tomography (OCT)
Description
Change from baseline to 6 months visit, post each treatment cycle retinal nerve fiber layer (RNFL) thickness in OCT, following treatment with intravenous or intrathecal MSC infusion, vs. placebo treatment in MS patients at 6 months post treatment. [An increase in RNFL thickness indicates clinical improvement]. * similar measurements will apply for Macula thickness
Time Frame
6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group
Title
Immunology
Description
Change from baseline to 6 months visit post each treatment cycle in the proportion of the lymphocytes expressing the CD4+CD25+ markers (T-regulatory cells) following treatment with intravenous or intrathecal MSC infusion, vs. placebo treatment at 6 months post treatment. [An increase in the proportion may indicate beneficial effects]. * similar measurements (for evaluation of safety of the treatment) will be performed for additional white blood cell subpopulations
Time Frame
6 months for each treatment cycle; the two cycles (each of 6 months duration) will be combined together and provide a single measurement for each group

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Consenting patients fulfilling the Poser's clinical criteria for definite MS Age: 18-65, males and females Duration of disease: >3 years Progressive form of MS: PPMS, SPMS (with/without relapses) EDSS score of 3.5 - 6.5 Failure to currently available, registered - first and second line immunomodulatory treatments (at least one). Evidence for new activity of MS during the 3 months before the injection of MSC. Exclusion Criteria: Patients who were treated with cytotoxic medications during the last 3 months prior to the inclusion. Patients suffering from significant cardiac, renal or hepatic failure or any other disease that may risk the patient or interfere with the ability to interpret the results Patients with active infections Patients with severe cognitive decline or inability to understand and sign the informed consent Patients who received any cellular treatment in the past
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Hadas Lemberg, PhD
Organizational Affiliation
Director, R&D Division
Official's Role
Study Chair
Facility Information:
Facility Name
Hadassah Medical Organization
City
Jerusalem
ZIP/Postal Code
91120
Country
Israel

12. IPD Sharing Statement

Citations:
PubMed Identifier
35641166
Citation
Petrou P, Kassis I, Ginzberg A, Hallimi M, Karussis D. Effects of Mesenchymal Stem Cell Transplantation on Cerebrospinal Fluid Biomarkers in Progressive Multiple Sclerosis. Stem Cells Transl Med. 2022 Mar 3;11(1):55-58. doi: 10.1093/stcltm/szab017.
Results Reference
derived
PubMed Identifier
33253391
Citation
Petrou P, Kassis I, Levin N, Paul F, Backner Y, Benoliel T, Oertel FC, Scheel M, Hallimi M, Yaghmour N, Hur TB, Ginzberg A, Levy Y, Abramsky O, Karussis D. Beneficial effects of autologous mesenchymal stem cell transplantation in active progressive multiple sclerosis. Brain. 2020 Dec 1;143(12):3574-3588. doi: 10.1093/brain/awaa333.
Results Reference
derived

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Clinical Efficacy of Autologous Mesenchymal Bone Marrow Stem Cells in Active & Progressive Multiple Sclerosis

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