Stem Cells in Rapidly Evolving Active Multiple Sclerosis

Phase 1

Completed

Conditions: Multiple Sclerosis

Interventions: Drug: Placebo
Drug: Mesenchymal stem cells

Registration Number: NCT01606215

Lead Sponsor: Imperial College London

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).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 21

Inclusion Criteria

Patients with clinically and radiologically active multiple sclerosis as defined by:

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.
Age 18 to 50 years.
Disease duration 2 to 10 years from diagnosis (inclusive).
Expanded Disability Status Scale (EDSS) 2.0 to 6.5 at screening evaluation.
≥ 1 GEL on MRI within 6 months prior to harvesting.
Adequate culture of a subject's MSCs and their release for clinical use.

Exclusion Criteria

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.
SPMS without relapses and without new lesions (GEL or T2 positive) at MRI in the last 18 months.
PPMS without positive CSF OCBs or without a GEL or new T2 lesion in the previous 18 months.
No gadolinium enhancing lesion(s) in the 3 months prior to bone marrow harvesting.
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.
Failure of bone marrow (BM) sample to generate MSCs suitable for clinical use within a specified time frame (4 weeks).
Treatment with any immunosuppressive therapy, including natalizumab and fingolimod, within the last 3 months.
Treatment with interferon-beta or glatiramer acetate within the last 1 month.
Treatment with alemtuzumab (campath-1H) within the last 2 years.
Prior treatment with total lymphoid irradiation and autologous or allogeneic hematopoietic stem cell transplantation.
Participation in clinical trials of any experimental drugs in the 6 months before study entry.
Corticosteroid treatment in the last 30 days.
Presence of any active or chronic infection.
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.
Severely limited life expectancy by any other co-morbid illness.
Abnormal blood counts, a history of myelodysplasia or other cytopenia.
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).
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.
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).
Inability to give written informed consent/comply with study procedures.
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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Suspension media administered at Week 0
mesenchymal stem cells	Mesenchymal stem cells	1-2 x106 MSCs/kg administered at Week 0

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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).
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).
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.
Relapses	6 months	number of relapses in MSC treatment group vs. placebo group in the first 6 months
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.