Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00781872 |
| Other study ID # |
MS22MSC-HMO-CTIL |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 1/Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
October 2006 |
| Est. completion date |
December 2009 |
Study information
| Verified date |
March 2021 |
| Source |
Hadassah Medical Organization |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Although, effective immunotherapies for MS exist which downregulate the anti-myelin
reactivity and reduce the rate of relapses of the disease, there is no effective means today
to stop the progression of disability and induce remyelination. Neuronal stem cells were
shown to possess the ability to restore neuronal activity and produce new neurons through
transdifferentiation. Various other types of stem cells were tested in animal models with
promising results, revealing a potential for restoration of the neurological function in
neuroimmune and neurodegenerative conditions. Adult bone marrow derived stromal cells (MSC)
were shown to induce similar (to neuronal stem cells) immunomodulatory and neuroregenerative
effects and were shown in our laboratory to induce neuroprotection in the animal model of
chronic experimental autoimmune encephalomyelitis (EAE). MSCs offer practical advantages for
clinical therapeutic applications, since they can be obtained from the adult bone marrow and
therefore the patient can be the donor for himself, without any danger for rejection of the
cells. In addition, MSCs carry a safer profile and are less prone to malignant
transformation.
Our initial clinical experience with 10 patients with ALS and 10 with multiple sclerosis show
that intravenous and intrathecal administration of MSCs is feasible and safe.
In this study we propose an explorative protocol with the injection of MSCs (both
intrathecally and intravenously) in patients with MS, in an effort to prevent further
neurodegeneration through neuroprotective mechanisms and induce neuroregeneration and
restoration of neuronal function.
The primary endpoint will be to further evaluate the safety and feasibility of the treatment
with MSC infusions, in MS patients. Additionally, the migration ability of the transplanted
cells will be evaluated by tagging MSCs with the superparamagnetic iron oxide particle
(Feridex) for detection by MRI. Clinically the patients will be followed by monthly
evaluations of the MS functional rating scale (EDSS) scale. The MRI, will be also used to
evaluate changes in the total volume of lesions in the brain and the degree of atrophy.
Significance: This project may provide information for possible therapeutic uses of this type
of bone marrow adult stem cells in MS but may also serve as a pilot platform and pave the
path for future applications of various types of stem cells in neurodegerative diseases, in
general.
Description:
This study, is designed as a phase 1/2 open-safety clinical trial. At its first phase, 15
consenting patients with MS are included.
Inclusion Criteria:
Consenting patients fulfilled the following 4 inclusion criteria for this study:
1. the clinical criteria of Poser et alfor definite MS;
2. men and nonpregnant women aged 25 to 65 years;
3. duration of disease longer than 5 years; and
4. failure to respond to the currently available and registered agents for MS (ie,
interferons, glatiramer acetate [Copaxone], and immuno-suppressors), as manifested by an
increase of at least 1 degree in the EDSS score during the past year or the appearance
of at least 2 major MS relapses during the same period.
Exclusion criteria:
1. patients who were treated with cytotoxic medications (ie, cyclophosphamide,
mitoxantrone, and azathioprine) during the 3 months before the trial;
2. patients with significant cardiac, renal, or hepatic failure or any other disease that
may interfere with the ability to interpret the results of the study;
3. patients with an active infection; and
4. patients who showed severe cognitive decline or were unable to understand and sign the
informed consent.
Bone marrow aspiration is performed under short general anesthesia with puncture from the
posterior superior iliac crest while the patient was lying in a left or a right lateral
position. Approximately 200 mL of bone marrow inocula are obtained from each patient.
MSC Preparation and Culture A culture of purified MSCs is prepared under aseptic conditions
(positively pressurized clean rooms) using filtered sterilized Dulbecco modified Eagle medium
with low glucose lev- els (Qiagen, Valencia, California) supplemented with 10% fetal bovine
serum, 1% L-glutamine, and 1% penicillin-streptomycin- nystatin solution (all from Biological
Industries, Kibbutz Beit- Haemek, Israel).
Mesenchymal cells are cultured for 40 to 60 days, until they reach confluency, and then
harvested and cryopreserved in 10% dimethyl sulfoxide-containing medium in liquid nitrogen
(-196°C). At 2 weeks, a sample is taken for sterility testing and quality control. After
sterility confirmed, the MSCs are transferred to the laboratory on dry ice, thawed in a 37°C
water bath, and washed twice with normal saline solution to remove any residual dimethyl
sulfoxide. The cells are then resuspended in normal saline at a concentration of 10x106/mL to
15x106/mL. Two-thirds of the total number of cells (usually 60x106 to 100x106) are injected
intrathecally, and one-third, intravenously. A sample of the cells to be injected is tested
by fluorescence-activated cell sorter (FACS) analysis; cells (98%) should express the surface
markers characteristic of MSCs (CD29, CD73, CD90, CD105, and CD166) and be negative for CD34,
CD45, and CD14.
Treatment Protocol All patients receive an intrathecal injection via a standard lumbar
puncture (mean of 1 million cells per Kg of body weight) and an intravenous injection of
0.3-1 million cells per kg, intravenously..
An extension phase is scheduled for patients completing the first phase of this trial as an
open prospective study with repeated intrathecal or intravenous injections of autologous MSC
in patients from the initial trial and 10 additional ones (total up to 24 patients) with
progressive forms of MS (secondary progressive, primary progressive or
relapsing-progressive). Patients should be defined as failures to first and second lines of
immunomodulatory treatments experiencing deterioration (at least 0.5 degree in the EDSS
scale) during the year preceding their inclusion to our study or had at least one major
relapse without sufficient recovery. Patients will be treated with 1x10 million MSC per kg of
body weight, intrathecally and intravenously and subsequently with up to 8 courses of IT- or
IV-injections of MSC (at the same dose), at intervals of 6-12 months. The duration of the
trial is 4 years.
Patients will be followed up every 3 months for the whole duration of the trial, for safety
assessment and changes in the disability scores (EDSS).
Immunological analysis will be performed at 4 time points (day 1, month 1, month 3 and month
6) following the first MSC-treatment and will include a fluorescent cell sorter (FACS)
analysis to evaluate the proportions of the lymphocytes expressing markers of immune
activation or of regulatory cell phenotype.
