Multiple Sclerosis
Conditions
Keywords
multiple sclerosis, mesenchymal stem cells, bone marrow, rapidly evolving
Brief summary
This is a randomised, double-blind crossover study to study the effect of intravenous treatment with autologous (derived from the individuals themselves) mesenchymal stem cells (MSCs) in patients with multiple sclerosis (MS).
Detailed description
Current treatments for MS target the immune system and are not curative. There is much interest in MSCs as they have the potential to not only affect the immune system but may also promote repair. This study will use MSCs that are harvested from the bone marrow and grown for up to 52 days before being given back to the person from whom they were harvested. This avoids any chemotherapy so is therefore safer than other types of stem cells. In this crossover study, everyone will receive their own stem cells back but in half of the patients it will be delayed by 24 weeks. The primary outcomes are to check that the procedure is safe and to measure any changes on the MRI at 24 weeks. Other more exploratory measures will try to assess effects on repair in the central nervous system (CNS).
Interventions
DRUGMesenchymal stem cells
1.0-2.0 million cells/kg body weight
DRUGPlacebo
Placebo
Sponsors
Imperial College London
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
Patients with clinically and radiologically active multiple sclerosis as defined by: 1. Diagnosis of MS: * Relapsing remitting MS (RRMS): ≥ 1 moderate-severe relapse and ≥1 GEL in past 18 months or ≥ 1 moderate-severe relapse and ≥1 new T2 lesion in past 18 months. * Secondary progressive MS (SPMS) with an increase of ≥ 1 EDSS point (if baseline EDSS ≤ 5) or 0.5 EDSS point (if baseline EDSS ≥ 5.5), in the previous 18 months and ≥ 1 GEL in past 18 months or ≥ 1 moderate-severe relapse and ≥1 new T2 lesion in past 18 months. * Primary progressive MS (PPMS) patients with positive oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF) and an increase of ≥ 1 EDSS point (if baseline EDSS is ≤ 5.0) or 0.5 EDSS point (if baseline EDSS is ≥ 5.5), or quantifiable, objective evidence of equivalent progression in the previous 18 months and ≥ 1 GEL in past 18 months or ≥ 1 new T2 lesion in past 18 months. 2. Age 18 to 50 years. 3. Disease duration 2 to 10 years from diagnosis (inclusive). 4. Expanded Disability Status Scale (EDSS) 2.0 to 6.5 at screening evaluation. 5. ≥ 1 GEL on MRI within 6 months prior to harvesting. 6. Adequate culture of a subject's MSCs and their release for clinical use.
Exclusion criteria
1. RRMS without at least one severe relapse in the previous 18 months or without at least one GEL or one new T2 in the previous 18 months. 2. SPMS without relapses and without new lesions (GEL or T2 positive) at MRI in the last 18 months. 3. PPMS without positive CSF OCBs or without a GEL or new T2 lesion in the previous 18 months. 4. No gadolinium enhancing lesion(s) in the 3 months prior to bone marrow harvesting. 5. A previously ineligible patient who failed to meet the MRI requirements of the inclusion criteria will not be reviewed again even if further imaging, revealing ≥ 1 GEL, becomes available. 6. Failure of bone marrow (BM) sample to generate MSCs suitable for clinical use within a specified time frame (4 weeks). 7. Treatment with any immunosuppressive therapy, including natalizumab and fingolimod, within the last 3 months. 8. Treatment with interferon-beta or glatiramer acetate within the last 1 month. 9. Treatment with alemtuzumab (campath-1H) within the last 2 years. 10. Prior treatment with total lymphoid irradiation and autologous or allogeneic hematopoietic stem cell transplantation. 11. Participation in clinical trials of any experimental drugs in the 6 months before study entry. 12. Corticosteroid treatment in the last 30 days. 13. Presence of any active or chronic infection. 14. Previous history of a malignancy other than basal cell carcinoma of the skin and carcinoma in situ that has been in remission for more than one year. 15. Severely limited life expectancy by any other co-morbid illness. 16. Abnormal blood counts, a history of myelodysplasia or other cytopenia. 17. Known pregnancy, positive urine pregnancy test at screening or risk or pregnancy (this includes patients who are unwilling to practice active contraception during the duration of the study). 18. Contraindication to MRI including but not limited to intracranial aneurysm clips (except Sugita), history of intra-orbital metal fragments that have not been removed by an MD (as confirmed by orbital X-Ray), pacemaker and non-MRI compatible devices (e.g. heart valves, inner ear implants), history of claustrophobia or the inability of the subject to lie still on their back for a period of 1.5 hours in the MRI scanner. 19. An estimated glomerular filtration rate (eGFR)\< 60 mL/min/1.73m2 or history or presence of renal impairment (e.g. serum creatinine clearance less than 30ml/min). 20. Inability to give written informed consent/comply with study procedures. 21. Any significant organ dysfunction or co-morbidity that the Investigators consider would put the subject at unacceptable risk by participating in the study or that would interfere with the functional assessments.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Adverse Events Assessed by CTCAE v4.0 | 24 weeks from baseline | The number of adverse events before crossover in the stem cell treatment group compared to the placebo group over the first 24 weeks (please refer to period 1 of the participant flow). |
| Number of GELs Newly Appearing at Weeks 4, 12 and 24 After MSC Therapy in the First 24 Weeks of Trial | Up to 24 weeks | Where GELs stands for gadolinium enhancing lesions and MSC for Mesenchymal Stem Cell. This was to evaluate the efficacy of autologous mesenchymal stem cells in MS patients, quantified by the reduction in the number of new gadolinium-enhancing lesions counted on MRI scans over 24 weeks and the total number of GELs counted over months 1, 3 and 6 will be compared between treatment groups. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Combined Unique MRI Activity | Weeks 4, 12 and 24 | To evaluate the efficacy of autologous mesenchymal stem cells in MS patients, quantified by the reduction in combined unique MRI activity on MRI scans over 24 weeks. The total number of such lesions counted over Weeks 4, 12 and 24 will be compared between treatment groups. Combined Unique MRI activity defined as number of new T1w contrast-enhanced lesions plus number of new T2w lesions without contrast enhancement on T1w plus number of enlarging T2w lesions (\>50% volume increase, no lesion fusion) without contrast enhancement on T1w. |
| Number of Newly Appearing GELs Over Months 1, 3 and 6 Will be Compared Between Treatment Groups. | Months 1, 3 and 6 | Number of gadolinium enhancing lesions identified over months 1, 3 and 6 will be compared between treatment groups - the treatment groups in this section relate to all 13 patients treated with MSCs (so patients in arm MSCs first, then placebo and 7 patients in placebo first, then MSCs) with 7 placebo patients (placebo first, then MSCs - the placebo group here ignores the 6 pts treated with MSCs first as we do not know whether there is any ongoing effect of MSCs beyond 24 weeks). |
| Progression of Disability | 6 months | EDSS at 6 months in both groups at Week 24: comparing 'MSCs first, then placebo' and 'Placebo first, then MSCs' at Week 24. EDSS is a disability score. EDSS is an abbreviation for Expanded Disability Status Scale. Ranges from 0 (no disability) to 10 (death). A higher score indicates worsening disability. |
| Relapses | 6 months | number of relapses in MSC treatment group vs. placebo group in the first 6 months |
| Comparison of Contrast Enhancing Lesions Between Treatment Periods Following Crossover | Months 6-12 | The number of contrast enhancing lesions counted over months 7, 9 and 12 (that is after cross-over). |
Countries
United Kingdom
Participant flow
Recruitment details
21 patients screened into trial and having bone marrow aspiration
Pre-assignment details
Bone marrow aspiration and expansion in the stem cell laboratory. Continuation in trial required expansion of MSCs to 1-2 x106 million MSCs/kg Of the 21 patients screened, only 13 continued in the trial (others failed MSC expansion and do not contribute to results)
Participants by arm
| Arm | Count |
|---|---|
| A: Mesenchymal Stem Cells First, Then Placebo Mesenchymal stem cells first, then placebo:
Mesenchymal stem cells; 1.0-2.0 million cells/kg body weight (1-2 x106 MSCs/kg administered at Week 0) | 6 |
| B: Placebo First, Then MSCs Placebo first, then MSCs:
Placebo; Placebo (Suspension media administered at Week 0) | 7 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment to 1st Group - Placebo to 2nd | Failure to expand autologous mesenchymal stem cell product according to protocol specifications | 4 | 4 |
Baseline characteristics
| Characteristic | A: Mesenchymal Stem Cells First, Then Placebo | B: Placebo First, Then MSCs | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 7 Participants | 13 Participants |
| Race/Ethnicity, Customized Ethnicity | 6 Participants | 6 Participants | 12 Participants |
| Race/Ethnicity, Customized Race | 6 Participants | 7 Participants | 13 Participants |
| Region of Enrollment United Kingdom | 6 participants | 7 participants | 13 participants |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 9 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 11 |
| other Total, other adverse events | 5 / 10 | 0 / 11 |
| serious Total, serious adverse events | 0 / 10 | 0 / 11 |
Outcome results
Primary
Number of Adverse Events Assessed by CTCAE v4.0
The number of adverse events before crossover in the stem cell treatment group compared to the placebo group over the first 24 weeks (please refer to period 1 of the participant flow).
Time frame: 24 weeks from baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A: Mesenchymal Stem Cells First, Then Placebo | Number of Adverse Events Assessed by CTCAE v4.0 | 5 total events |
| B: Placebo First, Then MSCs | Number of Adverse Events Assessed by CTCAE v4.0 | 0 total events |
Primary
Number of GELs Newly Appearing at Weeks 4, 12 and 24 After MSC Therapy in the First 24 Weeks of Trial
Where GELs stands for gadolinium enhancing lesions and MSC for Mesenchymal Stem Cell. This was to evaluate the efficacy of autologous mesenchymal stem cells in MS patients, quantified by the reduction in the number of new gadolinium-enhancing lesions counted on MRI scans over 24 weeks and the total number of GELs counted over months 1, 3 and 6 will be compared between treatment groups.
Time frame: Up to 24 weeks
Population: Comparison of GELs between MSC- vs placebo- treated groups up to Week 24
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| A: Mesenchymal Stem Cells First, Then Placebo | Number of GELs Newly Appearing at Weeks 4, 12 and 24 After MSC Therapy in the First 24 Weeks of Trial | Week 0 to 4 | 1.5 number of GELS counted | Standard Deviation 2.07 |
| A: Mesenchymal Stem Cells First, Then Placebo | Number of GELs Newly Appearing at Weeks 4, 12 and 24 After MSC Therapy in the First 24 Weeks of Trial | Week 4 to 12 | 1.5 number of GELS counted | Standard Deviation 2.25 |
| A: Mesenchymal Stem Cells First, Then Placebo | Number of GELs Newly Appearing at Weeks 4, 12 and 24 After MSC Therapy in the First 24 Weeks of Trial | Week 12 to 24 | 1.17 number of GELS counted | Standard Deviation 0.75 |
| B: Placebo First, Then MSCs | Number of GELs Newly Appearing at Weeks 4, 12 and 24 After MSC Therapy in the First 24 Weeks of Trial | Week 0 to 4 | 1.29 number of GELS counted | Standard Deviation 2.98 |
| B: Placebo First, Then MSCs | Number of GELs Newly Appearing at Weeks 4, 12 and 24 After MSC Therapy in the First 24 Weeks of Trial | Week 4 to 12 | 2.29 number of GELS counted | Standard Deviation 4.39 |
| B: Placebo First, Then MSCs | Number of GELs Newly Appearing at Weeks 4, 12 and 24 After MSC Therapy in the First 24 Weeks of Trial | Week 12 to 24 | 2.43 number of GELS counted | Standard Deviation 4.89 |
Comparison: Week 4 datap-value: 0.84t-test, 2 sided
Comparison: Week 12 datap-value: 0.62t-test, 2 sided
Comparison: Week 24 datap-value: 0.61t-test, 2 sided
Secondary
Combined Unique MRI Activity
To evaluate the efficacy of autologous mesenchymal stem cells in MS patients, quantified by the reduction in combined unique MRI activity on MRI scans over 24 weeks. The total number of such lesions counted over Weeks 4, 12 and 24 will be compared between treatment groups. Combined Unique MRI activity defined as number of new T1w contrast-enhanced lesions plus number of new T2w lesions without contrast enhancement on T1w plus number of enlarging T2w lesions (\>50% volume increase, no lesion fusion) without contrast enhancement on T1w.
Time frame: Weeks 4, 12 and 24
Population: after crossover treatment
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| A: Mesenchymal Stem Cells First, Then Placebo | Combined Unique MRI Activity | Week 24 | 1.83 combined unique MRI activity | Standard Deviation 1.6 |
| A: Mesenchymal Stem Cells First, Then Placebo | Combined Unique MRI Activity | Week 4 | 1.5 combined unique MRI activity | Standard Deviation 2.07 |
| A: Mesenchymal Stem Cells First, Then Placebo | Combined Unique MRI Activity | Week 12 | 2.17 combined unique MRI activity | Standard Deviation 3.07 |
| B: Placebo First, Then MSCs | Combined Unique MRI Activity | Week 24 | 4.43 combined unique MRI activity | Standard Deviation 8.9 |
| B: Placebo First, Then MSCs | Combined Unique MRI Activity | Week 4 | 2 combined unique MRI activity | Standard Deviation 3.7 |
| B: Placebo First, Then MSCs | Combined Unique MRI Activity | Week 12 | 3.14 combined unique MRI activity | Standard Deviation 5.05 |
Comparison: Week 4p-value: 0.77t-test, 2 sided
Comparison: Week 12p-value: 0.68t-test, 2 sided
Comparison: Week 24p-value: 0.48t-test, 2 sided
Secondary
Comparison of Contrast Enhancing Lesions Between Treatment Periods Following Crossover
The number of contrast enhancing lesions counted over months 7, 9 and 12 (that is after cross-over).
Time frame: Months 6-12
Population: crossover phase of trial; weeks 24-48
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| A: Mesenchymal Stem Cells First, Then Placebo | Comparison of Contrast Enhancing Lesions Between Treatment Periods Following Crossover | Week 28 | 2.5 number of GELS counted | Standard Deviation 2.35 |
| A: Mesenchymal Stem Cells First, Then Placebo | Comparison of Contrast Enhancing Lesions Between Treatment Periods Following Crossover | Week 36 | 2.33 number of GELS counted | Standard Deviation 2.94 |
| A: Mesenchymal Stem Cells First, Then Placebo | Comparison of Contrast Enhancing Lesions Between Treatment Periods Following Crossover | Week 48 | 1.5 number of GELS counted | Standard Deviation 1.87 |
| B: Placebo First, Then MSCs | Comparison of Contrast Enhancing Lesions Between Treatment Periods Following Crossover | Week 28 | 1.29 number of GELS counted | Standard Deviation 1.5 |
| B: Placebo First, Then MSCs | Comparison of Contrast Enhancing Lesions Between Treatment Periods Following Crossover | Week 36 | 2.29 number of GELS counted | Standard Deviation 3.25 |
| B: Placebo First, Then MSCs | Comparison of Contrast Enhancing Lesions Between Treatment Periods Following Crossover | Week 48 | 1.71 number of GELS counted | Standard Deviation 2.56 |
Secondary
Number of Newly Appearing GELs Over Months 1, 3 and 6 Will be Compared Between Treatment Groups.
Number of gadolinium enhancing lesions identified over months 1, 3 and 6 will be compared between treatment groups - the treatment groups in this section relate to all 13 patients treated with MSCs (so patients in arm MSCs first, then placebo and 7 patients in placebo first, then MSCs) with 7 placebo patients (placebo first, then MSCs - the placebo group here ignores the 6 pts treated with MSCs first as we do not know whether there is any ongoing effect of MSCs beyond 24 weeks).
Time frame: Months 1, 3 and 6
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| A: Mesenchymal Stem Cells First, Then Placebo | Number of Newly Appearing GELs Over Months 1, 3 and 6 Will be Compared Between Treatment Groups. | Week 12 to 24 | 1.46 number of GELS counted | Standard Deviation 1.9 |
| A: Mesenchymal Stem Cells First, Then Placebo | Number of Newly Appearing GELs Over Months 1, 3 and 6 Will be Compared Between Treatment Groups. | Week 0 to 4 | 1.38 number of GELS counted | Standard Deviation 1.71 |
| A: Mesenchymal Stem Cells First, Then Placebo | Number of Newly Appearing GELs Over Months 1, 3 and 6 Will be Compared Between Treatment Groups. | Week 4 to 12 | 1.92 number of GELS counted | Standard Deviation 2.75 |
| B: Placebo First, Then MSCs | Number of Newly Appearing GELs Over Months 1, 3 and 6 Will be Compared Between Treatment Groups. | Week 4 to 12 | 2.29 number of GELS counted | Standard Deviation 4.39 |
| B: Placebo First, Then MSCs | Number of Newly Appearing GELs Over Months 1, 3 and 6 Will be Compared Between Treatment Groups. | Week 12 to 24 | 2.43 number of GELS counted | Standard Deviation 4.89 |
| B: Placebo First, Then MSCs | Number of Newly Appearing GELs Over Months 1, 3 and 6 Will be Compared Between Treatment Groups. | Week 0 to 4 | 1.29 number of GELS counted | Standard Deviation 2.98 |
Secondary
Progression of Disability
EDSS at 6 months in both groups at Week 24: comparing 'MSCs first, then placebo' and 'Placebo first, then MSCs' at Week 24. EDSS is a disability score. EDSS is an abbreviation for Expanded Disability Status Scale. Ranges from 0 (no disability) to 10 (death). A higher score indicates worsening disability.
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| A: Mesenchymal Stem Cells First, Then Placebo | Progression of Disability | 4.0 score on a scale (EDSS) | Standard Deviation 1 |
| B: Placebo First, Then MSCs | Progression of Disability | 3.9 score on a scale (EDSS) | Standard Deviation 1.77 |
Secondary
Relapses
number of relapses in MSC treatment group vs. placebo group in the first 6 months
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| A: Mesenchymal Stem Cells First, Then Placebo | Relapses | 2 total events |
| B: Placebo First, Then MSCs | Relapses | 10 total events |