Multiple Sclerosis
Conditions
Keywords
Mesenchymal Stem Cells, Neural Progenitors, Autologous, Bone Marrow, Multiple Sclerosis
Brief summary
This is a phase II, double-blinded, placebo-controlled, randomized, cross-over Study designed to determine the efficacy of multiple intrathecal administrations of autologous mesenchymal stem cell-derived neural progenitor cells (MSC-NP) compared to placebo in patients with progressive multiple sclerosis. Efficacy will be measured through assessment of disability outcomes. Study participants will receive six intrathecal injections of culture-expanded autologous MSC-NPs at two month intervals in one year and six lumbar punctures as placebo treatments in a second year.
Detailed description
The IT-MSC-NP treatments and all clinical assessments will take place at a single center (Tisch MSRCNY). Study subjects will be assigned to blocks stratified by baseline EDSS score (3.0-4.0, 4.5-5.5, 6.0, and 6.5) and disease subtype (SPMS or PPMS). Study subjects are randomized in an equal fashion (1:1) to study treatment and placebo at initial randomization. Subjects in each block will be randomized into placebo or treatment group. In the second year, treated subjects will cross over to the placebo group and placebo subjects will cross over to the treated group. The total study duration will be 3 years upon enrollment. Each study subject will be required to attend up to 18 study visits, to include 1 screening visit, 1 bone marrow visit, 1 baseline visit, followed by study visits every 2 months during the treatment period of two years (12 treatment/LP procedure visits and 2 outcome visits), and an additional follow-up visit at the end of year 3.
Interventions
BIOLOGICALIntrathecal MSC-NP injection
MSC-NPs represent a neural subpopulation of MSCs from bone marrow with reduced pluripotency and minimized risk of ectopic differentiation, thus are likely to be more suitable for CNS delivery. Importantly, characterization of MSC-NPs demonstrated their immunoregulatory and trophic properties, and MSC-NPs derived from MS and non-MS patients alike were therapeutically viable.
Placebo
Sponsors
Tisch Multiple Sclerosis Research Center of New York
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Compassionate crossover design
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of MS as defined by the McDonald criteria * Diagnosis of primary progressive or secondary progressive MS * Between the ages of 18-65 years * Significant disability shown by an Expanded Disability Status Score (EDSS) of greater than or equal to 3.0, and less than or equal to 6.5, that was not acquired within the last 12 months. * Stable disease state as evidenced by a lack of gadolinium-enhancing lesions on an MRI and by a stable MRI disease burden (number of T2 lesions and size of lesions) in the last six months and no significant change in EDSS (1 point or more) in the last 12 months * Must agree to undergo four MRIs: at the time of enrollment, after year 1, after year 2, and after year 3 * Patients either within the geographical area or who are able to arrange reliable travel during the study period
Exclusion criteria
* EDSS greater than 6.5 * Duration of Disease \>20 years at time of screening * Change of disease modifying agent \< 12 months prior to beginning treatment. Additionally, no changes in disease modifying agent will be made during the course of the study. * Change in MS symptom management treatment \< 6 months prior to beginning treatment. Additionally, no changes in MS symptom management treatments will be made during the course of the study, unless there has been clinical improvement, in which case, a patient may discontinue a medication. * Start of any new orthotic device or durable medical equipment \< 6 months prior to beginning treatment or during the course of the study (patients may discontinue use of these devices during the course of the study if they show clinical improvement). * All patients who have ever been on Lemtrada (alemtuzumab) * All patients who have had any prior stem cell treatments, including HSCT * Pregnant or nursing mothers, or any woman intending to become pregnant in the next three years * All patients will have screening blood tests done. Only patients whose values are in the normal range as determined by the laboratory norms based on age and sex will be allowed to participate. Exceptions may be made for borderline normal laboratory values manifesting no clinical symptoms at the discretion of the Principal Investigator. * Use of systemic chemotherapeutic or anti-mitotic medications within three months of study start date due to the possibility of interference with bone marrow procedure * Any patients with a history of or with active malignancy * Use of steroids within three months of the study start date, as this would suggest an active disease state * History of cirrhosis due to increased risk of central nervous system (CNS) infection * Significantly uncontrolled hypertension because of increased risk for stroke or CNS hemorrhage. * Patients with active thyroid disease resulting in hyperthyroidism or hypothyroidism (Only well controlled patients with labs in the normal range will be included) because of hormone influence on cell growth * History of central nervous system infection or immunodeficiency syndromes due to increased risk of CNS infection * Preexisting blood disease (such as bone marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia) due to invasive nature of bone-marrow aspiration * Previous or current history of a coagulation disorder * Any metal implant in the body, which is contraindicated for MRI studies * Patients with alcohol or other substance abuse problems that may affect stem cell growth; habitual drug (including marijuana and nicotine) abusers, will be excluded from the study * Other major disease that, in the opinion of the Principal Investigator, would preclude participation in the study * Patients with Hepatitis B (HBV), Hepatitis C (HCV), syphilis, HIV-1, or HIV-2. * Any evidence of significant cognitive dysfunction based on a screening history and physical examination because it would preclude giving a truly informed consent * Patients who are enrolled in another clinical trial for MS treatment or who have received any study drug/biologics within the last 6 months. Additionally, while in the trial, patients may not enroll in any other clinical trial for MS or any other condition. * Patients who are anticipated to have difficultly accessing the intrathecal space related to scoliosis, obesity, or any other relevant factors determined by the PI.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Expanded Disability Status Scale (EDSS) Plus | Baseline and 13 months | Changes in disability assessed based on composite score of EDSS, timed 25-foot walk (T25FW), and nine hole peg test (9HPT) (EDSS-Plus). Improvement is defined by at least one of the following three measures: ≥0.5 decrease in EDSS (if EDSS at entry is ≥ 6.0) or ≥ 1.0 decrease in EDSS (if EDSS at entry is ≤5.5), ≥20% increase in T25FW, or ≥20% increase in 9HPT in either dominant or non-dominant hand. Assessments were made at baseline and month 13. The number of patients who improved in any of the 3 composite measures in month 13 compared to baseline is reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in EDSS From Baseline | Baseline and 13 months | The Expanded Disability Status Scale (EDSS) is a standardized measure used to assess and track the level of disability in people with multiple sclerosis (MS), ranging from 0 (normal neurological status) to 10 (death due to MS) in 0.5 increments. Only ambulatory subjects were enrolled in this study with an EDSS between 3.0 and 6.5. Subgroups of participants were analyzed based on the degree of walking disability. EDSS 3.0-5.5 represents moderate to severe disability but able to walk without assistance, and EDSS 6.0-6.5 represents a need for unilateral or bilateral assistance to ambulate. A decrease in EDSS at month 13 compared to baseline is considered improvement. |
| Percent Change in T25FW (Timed 25 Foot Walk) From Baseline | Baseline and 13 months | The timed 25-foot walk (T25FW) is a test used in multiple sclerosis (MS) to assess a person's mobility and leg function, where individuals walk 25 feet as quickly and safely as possible, and the time taken is recorded. A positive percentage change indicates improved walking in month 13 compared to baseline, whereas a negative percentage change indicates worsening. |
| Percent Change in 6MWT (6 Minute Walk Test) From Baseline | Baseline and 13 months | The 6-minute walk test (6MWT) in multiple sclerosis (MS) measures functional walking capacity by assessing the distance a person can walk in 6 minutes. A positive percentage change indicates improved walking capacity at month 13 compared to baseline, whereas a negative percentage change indicates worsening. |
| Change in Multiple Sclerosis Functional Composite (MSFC) Z-Score From Baseline | Baseline and 13 months | The Multiple Sclerosis Functional Composite (MSFC) is a standardized tool used to quantify disability in people with multiple sclerosis (MS) by measuring leg function/ambulation (timed 25 foot walk), arm/hand function (9-hole peg test), and cognitive function (Paced Auditory Serial Addition Test). Each assessment is converted into a Z score. A Z-score of 0 represents the population mean. The composite MSFC Z-score represents an average of the 3 Z-scores. A positive change in composite Z-score in month 13 compared to baseline represents better performance and a negative change in composite Z score indicates worse performance. |
| Percent Change in 9HPT-ND (9 Hole Peg Test in Non-Dominant Hand) From Baseline | Baseline and 13 months | The Nine-Hole Peg Test (9HPT) is a standardized, quantitative assessment used to measure manual dexterity and upper extremity function in individuals with multiple sclerosis (MS). Each hand, dominant (D) and non-dominant (ND) is assessed seperately. A positive percentage change indicates improved function at month 13 compared to baseline, whereas a negative percentage change indicates worsening. |
| Change in MSWS-12 (12 Item MS Walking Scale) Score From Baseline | Baseline and 13 months | The 12-item Multiple Sclerosis Walking Scale (MSWS-12) is a patient-reported outcome measure that assesses the impact of multiple sclerosis (MS) on walking ability. The self-administered questionnaire consists of 12 items addressing how MS has affected various aspects of walking over the past two weeks. Each of the 12 items is scored from 1 to 5 from: 1 = Not at all to 5 = Extremely. Raw total score ranges from 12 (no impairment) to 60 (maximum impairment). Raw score is converted to a standardized score (0-100 scale) producing a final score from 0 = No impact of MS on walking to 100 = Maximum impact. The change in score from baseline to post-intervention was calculated. A decrease in score at month 13 compared to baseline was considered improvement. |
| Change in PASAT (Paced Auditory Serial Addition Test) Score From Baseline | Baseline and 13 months | The Paced Auditory Serial Addition Test (PASAT) is a neuropsychological test used to assess cognitive impairments, attention, information processing speed, and working memory. The test involves listening to a series of single-digit numbers and the individual must add each new number to the one immediately before it. The score is the number of correct responses out of 60 items. The change in score from baseline to post-intervention is calculated. A positive change in score means an increase in the number of correct answers at month 13 compared to baseline, generally indicating improvement in information processing speed and sustained attention. |
| Percent Change in 9HPT-D (9 Hole Peg Test in Dominant Hand) From Baseline | Baseline and 13 months | The Nine-Hole Peg Test (9HPT) is a standardized, quantitative assessment used to measure manual dexterity and upper extremity function in individuals with multiple sclerosis (MS). Each hand, dominant (D) and non-dominant (ND) is assessed seperately. A positive percentage change indicates improved function at month 13 compared to baseline, whereas a negative percentage change indicates worsening. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment First, Then Placebo Participants will receive six intrathecal injections of autologous stem cells every 2 months over a year. After a 3 month pause, participants will crossover into the placebo group and receive six intrathecal injections of saline every 2 months over a year. | 27 |
| Placebo First, Then Treatment Participants will receive six intrathecal injections of saline every 2 months over a year. After a 3 month pause, participants will crossover into the treatment group and receive six intrathecal injections of autologous stem cells every 2 months over a year. | 27 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Year 1, First Intervention | pandemic travel limitation | 1 | 0 |
| Year 1, First Intervention | Protocol Violation | 1 | 0 |
| Year 1, First Intervention | Withdrawal by Subject | 1 | 0 |
| Year 2, Crossover Intervention | Adverse event as a result of long-COVID | 1 | 0 |
| Year 2, Crossover Intervention | failure to isolate MSCs from bone marrow | 0 | 1 |
| Year 2, Crossover Intervention | pandemic travel limitation | 1 | 0 |
| Year 2, Crossover Intervention | severe COVID | 0 | 1 |
Baseline characteristics
| Characteristic | Treatment First, Then Placebo | Placebo First, Then Treatment | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants | 26 Participants | 53 Participants |
| Age, Continuous | 51 years STANDARD_DEVIATION 7 | 49 years STANDARD_DEVIATION 9 | 50 years STANDARD_DEVIATION 8 |
| Baseline EDSS (expanded disability status scale) EDSS 3.0-5.5 | 14 Participants | 14 Participants | 28 Participants |
| Baseline EDSS (expanded disability status scale) EDSS 6.0-6.5 | 13 Participants | 13 Participants | 26 Participants |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 18 Participants | 20 Participants | 38 Participants |
| Sex: Female, Male Male | 9 Participants | 7 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 27 | 0 / 27 | 0 / 27 | 0 / 24 |
| other Total, other adverse events | 24 / 27 | 15 / 27 | 20 / 27 | 13 / 24 |
| serious Total, serious adverse events | 2 / 27 | 0 / 27 | 3 / 27 | 3 / 24 |
Outcome results
Primary
Expanded Disability Status Scale (EDSS) Plus
Changes in disability assessed based on composite score of EDSS, timed 25-foot walk (T25FW), and nine hole peg test (9HPT) (EDSS-Plus). Improvement is defined by at least one of the following three measures: ≥0.5 decrease in EDSS (if EDSS at entry is ≥ 6.0) or ≥ 1.0 decrease in EDSS (if EDSS at entry is ≤5.5), ≥20% increase in T25FW, or ≥20% increase in 9HPT in either dominant or non-dominant hand. Assessments were made at baseline and month 13. The number of patients who improved in any of the 3 composite measures in month 13 compared to baseline is reported.
Time frame: Baseline and 13 months
Population: There is no washout period after stem cell injections, therefore outcome measures in participants receiving placebo second in the sequence (treatment first, then placebo) may reflect sustained effects of stem cell treatment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Treatment (IT MSC-NP) | Expanded Disability Status Scale (EDSS) Plus | 17 Participants |
| Placebo (IT Saline) | Expanded Disability Status Scale (EDSS) Plus | 17 Participants |
p-value: 1Fisher Exact
Secondary
Change in EDSS From Baseline
The Expanded Disability Status Scale (EDSS) is a standardized measure used to assess and track the level of disability in people with multiple sclerosis (MS), ranging from 0 (normal neurological status) to 10 (death due to MS) in 0.5 increments. Only ambulatory subjects were enrolled in this study with an EDSS between 3.0 and 6.5. Subgroups of participants were analyzed based on the degree of walking disability. EDSS 3.0-5.5 represents moderate to severe disability but able to walk without assistance, and EDSS 6.0-6.5 represents a need for unilateral or bilateral assistance to ambulate. A decrease in EDSS at month 13 compared to baseline is considered improvement.
Time frame: Baseline and 13 months
Population: There is no washout period after stem cell injections, therefore outcome measures in participants receiving placebo second in the sequence (treatment first, then placebo) may reflect sustained effects of stem cell treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (IT MSC-NP) | Change in EDSS From Baseline | -0.12 change in score on a scale | Standard Deviation 0.67 |
| Placebo (IT Saline) | Change in EDSS From Baseline | -0.15 change in score on a scale | Standard Deviation 0.77 |
p-value: 0.4Wilcoxon (Mann-Whitney)
Secondary
Change in MSWS-12 (12 Item MS Walking Scale) Score From Baseline
The 12-item Multiple Sclerosis Walking Scale (MSWS-12) is a patient-reported outcome measure that assesses the impact of multiple sclerosis (MS) on walking ability. The self-administered questionnaire consists of 12 items addressing how MS has affected various aspects of walking over the past two weeks. Each of the 12 items is scored from 1 to 5 from: 1 = Not at all to 5 = Extremely. Raw total score ranges from 12 (no impairment) to 60 (maximum impairment). Raw score is converted to a standardized score (0-100 scale) producing a final score from 0 = No impact of MS on walking to 100 = Maximum impact. The change in score from baseline to post-intervention was calculated. A decrease in score at month 13 compared to baseline was considered improvement.
Time frame: Baseline and 13 months
Population: There is no washout period after stem cell injections, therefore outcome measures in participants receiving placebo second in the sequence (treatment first, then placebo) may reflect sustained effects of stem cell treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (IT MSC-NP) | Change in MSWS-12 (12 Item MS Walking Scale) Score From Baseline | -.15 change in score | Standard Deviation 12.2 |
| Placebo (IT Saline) | Change in MSWS-12 (12 Item MS Walking Scale) Score From Baseline | -.15 change in score | Standard Deviation 15.1 |
p-value: 0.71Wilcoxon (Mann-Whitney)
Secondary
Change in Multiple Sclerosis Functional Composite (MSFC) Z-Score From Baseline
The Multiple Sclerosis Functional Composite (MSFC) is a standardized tool used to quantify disability in people with multiple sclerosis (MS) by measuring leg function/ambulation (timed 25 foot walk), arm/hand function (9-hole peg test), and cognitive function (Paced Auditory Serial Addition Test). Each assessment is converted into a Z score. A Z-score of 0 represents the population mean. The composite MSFC Z-score represents an average of the 3 Z-scores. A positive change in composite Z-score in month 13 compared to baseline represents better performance and a negative change in composite Z score indicates worse performance.
Time frame: Baseline and 13 months
Population: There is no washout period after stem cell injections, therefore outcome measures in participants receiving placebo second in the sequence (treatment first, then placebo) may reflect sustained effects of stem cell treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (IT MSC-NP) | Change in Multiple Sclerosis Functional Composite (MSFC) Z-Score From Baseline | -.13 change in composite z score | Standard Deviation 0.85 |
| Placebo (IT Saline) | Change in Multiple Sclerosis Functional Composite (MSFC) Z-Score From Baseline | -.06 change in composite z score | Standard Deviation 0.3 |
p-value: 0.28Wilcoxon (Mann-Whitney)
Secondary
Change in PASAT (Paced Auditory Serial Addition Test) Score From Baseline
The Paced Auditory Serial Addition Test (PASAT) is a neuropsychological test used to assess cognitive impairments, attention, information processing speed, and working memory. The test involves listening to a series of single-digit numbers and the individual must add each new number to the one immediately before it. The score is the number of correct responses out of 60 items. The change in score from baseline to post-intervention is calculated. A positive change in score means an increase in the number of correct answers at month 13 compared to baseline, generally indicating improvement in information processing speed and sustained attention.
Time frame: Baseline and 13 months
Population: There is no washout period after stem cell injections, therefore outcome measures in participants receiving placebo second in the sequence (treatment first, then placebo) may reflect sustained effects of stem cell treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (IT MSC-NP) | Change in PASAT (Paced Auditory Serial Addition Test) Score From Baseline | 2.3 change in score | Standard Deviation 5.5 |
| Placebo (IT Saline) | Change in PASAT (Paced Auditory Serial Addition Test) Score From Baseline | 1.4 change in score | Standard Deviation 8.2 |
p-value: 0.16Wilcoxon (Mann-Whitney)
Secondary
Percent Change in 6MWT (6 Minute Walk Test) From Baseline
The 6-minute walk test (6MWT) in multiple sclerosis (MS) measures functional walking capacity by assessing the distance a person can walk in 6 minutes. A positive percentage change indicates improved walking capacity at month 13 compared to baseline, whereas a negative percentage change indicates worsening.
Time frame: Baseline and 13 months
Population: There is no washout period after stem cell injections, therefore outcome measures in participants receiving placebo second in the sequence (treatment first, then placebo) may reflect sustained effects of stem cell treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (IT MSC-NP) | Percent Change in 6MWT (6 Minute Walk Test) From Baseline | -15.9 % change | Standard Deviation 33.9 |
| Placebo (IT Saline) | Percent Change in 6MWT (6 Minute Walk Test) From Baseline | -13.5 % change | Standard Deviation 29.7 |
p-value: 0.43Wilcoxon (Mann-Whitney)
Secondary
Percent Change in 9HPT-D (9 Hole Peg Test in Dominant Hand) From Baseline
The Nine-Hole Peg Test (9HPT) is a standardized, quantitative assessment used to measure manual dexterity and upper extremity function in individuals with multiple sclerosis (MS). Each hand, dominant (D) and non-dominant (ND) is assessed seperately. A positive percentage change indicates improved function at month 13 compared to baseline, whereas a negative percentage change indicates worsening.
Time frame: Baseline and 13 months
Population: There is no washout period after stem cell injections, therefore outcome measures in participants receiving placebo second in the sequence (treatment first, then placebo) may reflect sustained effects of stem cell treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (IT MSC-NP) | Percent Change in 9HPT-D (9 Hole Peg Test in Dominant Hand) From Baseline | -2.1 % change | Standard Deviation 18.1 |
| Placebo (IT Saline) | Percent Change in 9HPT-D (9 Hole Peg Test in Dominant Hand) From Baseline | -2.9 % change | Standard Deviation 17.9 |
p-value: 0.77Wilcoxon (Mann-Whitney)
Secondary
Percent Change in 9HPT-ND (9 Hole Peg Test in Non-Dominant Hand) From Baseline
The Nine-Hole Peg Test (9HPT) is a standardized, quantitative assessment used to measure manual dexterity and upper extremity function in individuals with multiple sclerosis (MS). Each hand, dominant (D) and non-dominant (ND) is assessed seperately. A positive percentage change indicates improved function at month 13 compared to baseline, whereas a negative percentage change indicates worsening.
Time frame: Baseline and 13 months
Population: There is no washout period after stem cell injections, therefore outcome measures in participants receiving placebo second in the sequence (treatment first, then placebo) may reflect sustained effects of stem cell treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (IT MSC-NP) | Percent Change in 9HPT-ND (9 Hole Peg Test in Non-Dominant Hand) From Baseline | -4.4 % change | Standard Deviation 30 |
| Placebo (IT Saline) | Percent Change in 9HPT-ND (9 Hole Peg Test in Non-Dominant Hand) From Baseline | -4.1 % change | Standard Deviation 15 |
p-value: 0.16Wilcoxon (Mann-Whitney)
Secondary
Percent Change in T25FW (Timed 25 Foot Walk) From Baseline
The timed 25-foot walk (T25FW) is a test used in multiple sclerosis (MS) to assess a person's mobility and leg function, where individuals walk 25 feet as quickly and safely as possible, and the time taken is recorded. A positive percentage change indicates improved walking in month 13 compared to baseline, whereas a negative percentage change indicates worsening.
Time frame: Baseline and 13 months
Population: There is no washout period after stem cell injections, therefore outcome measures in participants receiving placebo second in the sequence (treatment first, then placebo) may reflect sustained effects of stem cell treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (IT MSC-NP) | Percent Change in T25FW (Timed 25 Foot Walk) From Baseline | -14.4 % change | Standard Deviation 41.1 |
| Placebo (IT Saline) | Percent Change in T25FW (Timed 25 Foot Walk) From Baseline | -19.8 % change | Standard Deviation 49.2 |
p-value: 0.88Wilcoxon (Mann-Whitney)