Background
Methods/design
The MESEMS trial
The MESEMS network
Financial support
MESEMS trial design
Aim | Measures |
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Safety of IV therapy with autologous BM-derived MSC in RRMS, SPMS, and PPMS subjects | Number and severity of AEs within each treatment arm |
Activity of autologous BM-derived MSCs in MS subjects | Reduction compared to placebo in the total number of contrast-enhancing lesions (GEL) at MRI acquired on conventional MRI scans (minimum magnetic field intensity 1.5 T) over 24 weeks |
Aim | Measures |
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To compare the number of active MRI lesions in the placebo vs active treatment periods in both groups | Number of GEL counted over weeks 28, 36, and 48 (cross-over re-treatment) compared with the number of GEL counted over 4, 12, and 24 weeks (placebo vs active treatment periods) within each group |
To evaluate efficacy of MSC in reducing combined MRI activity and volume of black holes (BH) in both treatment groups at 24 weeks | Combined unique MRI activity (number of new or enlarging T2w, or enhancing or re-enhancing lesions) and volume of GEL over 4, 12, and 24 weeks compared between treatment groups. Volume of BH over 24 weeks compared between treatment groups |
To compare combined MRI activity and volume of BH in the placebo vs active treatment periods in both groups | Combined unique MRI activity and volume of GEL over weeks 28, 36, and 48 (cross-over re-treatment) compared with the same outcomes over 4, 12, and 24 weeks (placebo vs active treatment periods) within each group. Volume of BH over week 48 (cross-over re-treatment) compared with the same outcome over week 24 week (placebo vs active treatment periods) within each group |
To evaluate efficacy of MSC in reducing the volume of T2 lesions in both treatment groups at 24 weeks | Volume of T2w lesions over 24 weeks compared between treatment groups |
To compare the volume of T2 lesions in the placebo vs active treatment periods in both groups | Volume of T2w lesions over week 48 (cross-over re-treatment) compared with the same outcome over week 24 week (placebo vs active treatment periods) within each group |
To evaluate efficacy of MSC in reducing relapses at 24 weeks and to compare the number of relapses in the placebo vs active treatment periods in both groups | Number of relapses in MSC treatment group vs placebo group in the first 24 weeks and after cross-over re-treatment in the two groups (see below for definition of relapse) |
To evaluate efficacy of MSC in reducing the time to sustained progression of disability and increasing the number of progression-free patients at 24 weeks and to compare the time to sustained progression of disability and the proportion of progression-free patients in the placebo vs active treatment periods in both groups* | Time to sustained progression of disability and proportion of progression-free patients compared between treatment groups during the first 24 weeks and after cross-over re-treatment in the two groups |
To evaluate efficacy of MSC in increasing the number of progression-free patients at 24 weeks and to compare the proportion of disease-free patients in the placebo vs active treatment periods in both groups§ | Proportion of disease-free patients compared between treatment groups during the first 24 weeks and after cross-over re-treatment in the two groups |
To evaluate the efficacy of MSC treatment in clinical scores such a Multiple Sclerosis Functional Composite (MSFC) score and Symbol Digit Modalities Test (SDMT) score | Changes in MSFC and SDMT scores in the MSC treated group vs placebo group during the first 24 weeks and after cross-over re-treatment in the two groups |
Inclusion criteria
Italy | Spain–Andalusia | Copenhagen | London | Stockholm | Toulouse | Spain–Catalonia | Salzburg | Tehran | |
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RRMS with: | |||||||||
≥ 1 clinically documented relapse in past 12 months | x | x | See below | See below | x | x | x | x | |
≥ 2 clinically documented relapses in last 24 months | x | x | x | x | x | x | x | ||
≥ 1 GEL at MRI performed within the last 12 months or new T2 lesion at MRI performed within the last 12 months compared to a previous MRI performed within the last 12 months. | x | x | x | x | x | x | x | ||
London: ≥ 1 moderate-severe relapse AND (1 or more GELs in past 18 months OR ≥ 1 new T2 lesion). PLUS: ≥ 1 on MRI within 3 months prior to harvesting | |||||||||
Copenhagen ≥ 1 moderate-severe relapse in past 18 months OR ≥ 1 GEL (double-triple Gad) OR ≥ 1 new T2 | |||||||||
SPMS with: | |||||||||
An increase of ≥ 1 EDSS point (if at randomization EDSS ≤ 5.0) or 0.5 EDSS point (if at randomization EDSS ≥ 5.5) in the last 12 months AND ≥ 1 clinically documented relapse or ≥ 1 GEL at MRI within the last 12 months | x | x | No SPMS | See below | x | x | x | x | x |
Other (specify) | London: Changes in EDSS relate to previous 18 months AND 1(+) GELs in last 18 months or require SPMS with 1(+) relapses and 1(+) T2 lesions in past 18 months | ||||||||
PPMS with: | |||||||||
An increase of ≥ 1 EDSS point (if at randomization EDSS ≤ 5.0) or 0.5 EDSS point (if at randomization EDSS ≥ 5.5), in the last 12 months | x | x | No PPMS | See below | x | x | x | x | x |
AND ≥ 1 GEL at MRI performed within the last 12 months | x | x | x | x | x | x | x | ||
AND Positive cerebrospinal fluid (CSF) (oligoclonal banding) | x | x | x | x | x | x | x | ||
London: EDSS changes, GELs, or T2 lesions over last 18 months. PLUS: ≥ 1 on MRI within 3 months prior to harvesting |
MSC preparation and culture
Characteristics of the final MSC product
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CD105 expression ≥ 70%
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CD73 expression ≥ 70%
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CD90 expression ≥ 70%
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CD14 expression ≤ 10%
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CD45 expression ≤ 10%
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CD34 expression ≤ 10%
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Viability ≥ 80% at the time of freezing and in an aliquot thawed 2–3 weeks after freezing
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Detection of ≥ 70% expression of CD73, CD90, and CD105 in an aliquot thawed 2–3 weeks after freezing
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Lack of colony forming capacity in methylcellulose
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Lack of abnormal karyotype detected in at least 20 metaphases analyzed (unless an insufficient number of metaphases is obtained due to low cell growth as evidenced by the mitotic index)
Statistical analysis
Sample size
Data analysis
Assessment of inter-center differences
Treatment of relapses
Prohibited concomitant medications
Centralized study procedures
Centralized randomization and data entry
Centralized reading of the MRI
On-site procedures
Bone marrow harvest
Administration of the investigational product
Follow-up visits
Monitoring of AE
All AE
Severity
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Mild (grade 1): Awareness of signs or symptoms, but easily tolerated
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Moderate (grade 2): Discomfort enough to cause interference with normal daily activities
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Severe (grade 3): Inability to perform normal daily activities
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Life threatening (grade 4): Immediate risk of death from the reaction as it occurred
Causality
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None: No relationship between the experience and the administration of the study drug; related to other etiologies such as concomitant medications or patient’s clinical state.
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Unlikely: The current state of knowledge indicates that the relationship is unlikely.
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Possible: A reaction that follows a plausible temporal sequence from administration of the study drug and follows a known response pattern to the suspected study drug. The reaction might also have been produced by the patient’s clinical state or other modes of therapy administered to the patient.
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Probable: A reaction that follows a plausible temporal sequence from administration of the study drug and follows a known response pattern to the suspected study drug. The reaction cannot be reasonably explained by the known characteristics of the patient’s clinical state or other modes of therapy administered to the patient.
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Definite: An AE which is listed as a possible adverse reaction and cannot be reasonably explained by an alternative explanation, e.g., concomitant drug(s), concomitant disease(s).
Serious adverse events
Monitoring
Patient confidentiality
Premature closure of the study
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Treatment-related mortality: in case of one fatal accident 24 h after treatment, the IDSMC will evaluate the case and decide whether the trial should be stopped. The trial is stopped after the second fatal event 24 h after treatment.
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Determination of unexpected, significant, or unacceptable risk to patients.
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Failure to enter patients at an acceptable rate.
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Insufficient adherence to protocol requirements.
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Insufficient complete and/or valuable data.
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Protocol violation.
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Administrative decision.
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New data able to influence the willingness of the investigators to pursue the study.