E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
There are two co-primary objectives.
The first is to assess the safety of intravenous therapy with autologous (derived from the individuals themselves) MSCs in MS patients.
The second is to evaluate the activity of autologous MSCs in MS patients, quantified by the reduction in the number of new contrast-enhancing lesions on MRI scans over 24 weeks, the latter suggesting new inflammation.
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are to gather preliminary information about the efficacy of the experimental treatment in terms of combined MRI activity, MRI measures of remyelination (i.e. repair), clinical activity (incidence of relapses and disability progression in the MS patients), evaluating results of the Mantoux skin test (this is being used as a way of assessing the effect of the MSCs within the patient), and on immunological markers to be measured in blood and spinal fluid samples. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients with clinically and radiologically active multiple sclerosis as defined by:
1. Diagnosis of MS:
a. 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.
b. 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.
c. 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. EDSS 3.0 to 6.5 at screening evaluation.
5. ≥1 GEL on MRI within 3 months prior to harvesting.
6. Adequate culture of a subject’s MSCs and their release for clinical use.
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E.4 | Principal 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 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-MR 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.
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E.5 End points |
E.5.1 | Primary end point(s) |
There are two co-primary objectives:
The first is to assess the safety of intravenous autologous MSCs in MS patients - hence the number, time-frame of occurrence and severity of adverse events in the MSC treatment group will be compared to the placebo group.
The second is to evaluate the efficacy of autologous MSCs in MS patients, quantified by the reduction in the number of new contrast-enhancing lesions (GEL) on MRI scans over 24 weeks and the total number of GEL counted over months 1, 3 and 6 will be compared between treatment groups.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Week 0, 4, 12, 24, 28, 36 and 48 for MRI Safety will be evaluated at every visit throughout the 48 week study |
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E.5.2 | Secondary end point(s) |
Secondary endpoints: • volume of GEL identified over months 1, 3 and 6 will be compared between treatment groups. • number of GEL counted over months 7, 9 and 12 (cross-over re-treatment) compared between treatment periods (placebo vs. active treatment) for each patient. • combined unique MRI activity (number of new or enlarging T2, or enhancing or re-enhancing lesions). • number of relapses in MSC treatment group vs. placebo group in the first 6 months and after cross-over re-treatment in the two groups (see below for the definition of a relapse). • time to sustained progression of disability (RRMS group) (see below for definition of sustained EDSS progression) and proportion of progression-free patients. • proportion of disease-free patients (i.e. patients without relapses) and progression of MRI activity in the two groups. • changes in the Multiple Sclerosis Functional Composite (MSFC) score in MSC treatment group compared to the placebo group. • effect of MSCs on the peripheral immune responses. • effect of MSCs on delayed type hypersensitivity (Type 1V hypersensitivity) reaction as measured by the Mantoux test |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Weeks 0, 4, 12, 24, 28, 36 and 48. The Mantoux test will be performed at weeks -8, 0 and 24 weeks and evaluated 48-72 hours thereafter. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |