Multiple SclerosisPhase 2NCT00342134
Immunological Mechanisms of Hematopoietic Stem Cell Transplantation in Multiple Sclerosis
A Phase 2 study testing Stem Cell Transplanataion in people with Multiple Sclerosis, run by National Institute of Neurological Disorders and Stroke (NINDS) at 2 sites in United States.
Trial summary
Our goal is the elucidation of the mechanisms of action of autologous hematopoietic stem cell transplant (HSCT) and immunoablation by high-dose cyclophosphamide in multiple sclerosis (MS). Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Multiple Sclerosis
- What is being tested?
- Stem Cell Transplanataion
- Type of treatment
- Surgery or procedure
- How many people
- 34 participants
- Where
- 2 sitesUnited States
- Study dates
- 1 May 2002to 4 May 2011
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Males and females between the ages of 18 and 70 years, inclusive.
- Diagnosis of clinically definite MS according to the McDonald Criteria.
- Must have been on conventional immunomodulatory treatment (interferon beta or glatiramer acetate for at least 3 months OR have not tolerated conventional treatment OR have refused to start conventional treatment).
- Two or more total gadolinium enhancing lesions on each of two pretreatment MRI scans at screening and enrollment OR one large enhancing lesion measuring at least 1 cm refractory treatment with IV steroids on each of the two pre-treatment scans.
- Subject must have EDSS ranging from 1.5 to 6.5.
- Subject must have had at least one clinical exacerbation in the last year, and this must have occurred after having been on Avonex, Betaseron, Copaxone or Rebif therapy for at least 3 months. This does not apply if subject has refused to start conventional therapy.
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- Subject must have had a sustained (greater than or equal to 3 months) increase of greater than or equal to 1.0 on the EDSS (historical estimate allowed) between 1.5 and 5.5 or greater than or equal to 0.5 between 5.5 and 6.5 in the preceding year.
- Written informed consent prior to any testing under this protocol, including screening tests and evaluations that are not considered part of the subject's routine care.
- Women of childbearing potential should have a negative pregnancy test prior to entry in to the study.
Who cannot join
- Any risk of pregnancy - ALL female patients must have an effective means of birth control or be infertile due to hysterectomy, fallopian tube surgery, or premature menopause.
- Cardiac ejection fraction of less than 45 percent.
- Serum creatinine greater than 2.0.
- Patients who are pre-terminal or moribund.
- Bilirubin greater than 2.0, transaminases greater than 2 times normal.
- Patients with EDSS less than 1.5 or greater than 6.5.
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- Patients with pacemakers or implants who cannot get serial MRIs.
- Patients with active infections until infection is resolved.
- Patients with WBC count less than 3000 cells per microliter, platelets less than 100,000 cells per microliter and untransfused hemoglobin less than 10 grams per deciliter.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Johns Hopkins University
Baltimore, Maryland, 21205
Northwestern University
Chicago, Illinois, 60611
About this study
Official title: Immunological Mechanisms of Immune Ablation and Autologous Hematopoietic Stem Cell Transplantation in Secondary Progressive Multiple Sclerosis
Our goal is the elucidation of the mechanisms of action of autologous hematopoietic stem cell transplant (HSCT) and immunoablation by high-dose cyclophosphamide in multiple sclerosis (MS).
The molecular pathogenesis of multiple sclerosis is poorly understood although T-cell mediated immune destruction of myelin is thought to be an important element. We hypothesize, and the results of previous studies suggest, that radical immuno-ablation characterized by a profound T cell depletion can arrest the progression of disease. Patients with MS with poor prognosis based on the rate of progression and refractoriness to approved treatments (interferon-beta, glatiramer acetate) will be enrolled in clinical trials at the collaborating institution (NWU-Dr. R. Burt; Dr. D Kerr, JHU) and will receive either immune ablation with cyclophosphamide and the antibody Campath-1 followed by reconstitution with autologous peripheral blood stem cells, a procedure similar to autologous bone marrow transplantation, or high-dose cyclophosphamide treatment without stem cell rescue. While the overall treatment-related mortality worldwide is approximately 10%, the collaborating institution and investigators have an outstanding safety record in performing the procedure with no fatal adverse events after having transplanted more than 30 transplants with a previously more aggressive regimen than the one that is in use now. The underlying rationale for this treatment is that immuno-ablation could eliminate myelin-reactive T cells which, in disease-susceptible individuals, may have been activated by previous exposure to environmental agents or other acquired mechanisms of immune dysregulation.
In the proposed study we plan to address whether HSCT or immunoablation without stem cell rescue act beneficially in MS via the eradication of myelin-reactive T cells and reconstitution of a functional and non-autoimmune immune repertoire. To achieve this goal, we will compare peripheral blood T cell reactivities to myelin antigens before and after the treatment in 34 patients with MS. In parallel, to identify potential disease-mediating cells that do not recognize these myelin antigens, we will search for clonally expanded cells in the blood of MS patients before treatment employing molecular analysis of T cell receptor repertoire. Expanded T cell clones will be tracked during post-transplant follow-up of patients. If the eradication of certain clonotypes resulting from immuno-ablation correlates with disease remission, we will attempt to isolate these cells in culture from pre-treatment samples and determine their specificity using combinatorial peptide libraries. We would use the same approach in case of reappearance or new clonal expansions concomitant to disease relapses. We will combine these studies with a broader, unbiased approach that employs microarray technology to identify potential changes in gene expression profiles. This approach may also lead to the identification of novel therapeutic targets for pharmacological treatment.
Read the detailed description
Our goal is the elucidation of the mechanisms of action of autologous hematopoietic stem cell transplant (HSCT) and immunoablation by high-dose cyclophosphamide in multiple sclerosis (MS).
The molecular pathogenesis of multiple sclerosis is poorly understood although T-cell mediated immune destruction of myelin is thought to be an important element. We hypothesize, and the results of previous studies suggest, that radical immuno-ablation characterized by a profound T cell depletion can arrest the progression of disease. Patients with MS with poor prognosis based on the rate of progression and refractoriness to approved treatments (interferon-beta, glatiramer acetate) will be enrolled in clinical trials at the collaborating institution (NWU-Dr. R. Burt; Dr. D Kerr, JHU) and will receive either immune ablation with cyclophosphamide and the antibody Campath-1 followed by reconstitution with autologous peripheral blood stem cells, a procedure similar to autologous bone marrow transplantation, or high-dose cyclophosphamide treatment without stem cell rescue. While the overall treatment-related mortality worldwide is approximately 10%, the collaborating institution and investigators have an outstanding safety record in performing the procedure with no fatal adverse events after having transplanted more than 30 transplants with a previously more aggressive regimen than the one that is in use now. The underlying rationale for this treatment is that immuno-ablation could eliminate myelin-reactive T cells which, in disease-susceptible individuals, may have been activated by previous exposure to environmental agents or other acquired mechanisms of immune dysregulation.
In the proposed study we plan to address whether HSCT or immunoablation without stem cell rescue act beneficially in MS via the eradication of myelin-reactive T cells and reconstitution of a functional and non-autoimmune immune repertoire. To achieve this goal, we will compare peripheral blood T cell reactivities to myelin antigens before and after the treatment in 34 patients with MS. In parallel, to identify potential disease-mediating cells that do not recognize these myelin antigens, we will search for clonally expanded cells in the blood of MS patients before treatment employing molecular analysis of T cell receptor repertoire. Expanded T cell clones will be tracked during post-transplant follow-up of patients. If the eradication of certain clonotypes resulting from immuno-ablation correlates with disease remission, we will attempt to isolate these cells in culture from pre-treatment samples and determine their specificity using combinatorial peptide libraries. We would use the same approach in case of reappearance or new clonal expansions concomitant to disease relapses. We will combine these studies with a broader, unbiased approach that employs microarray technology to identify potential changes in gene expression profiles. This approach may also lead to the identification of novel therapeutic targets for pharmacological treatment.
- Conditions
- Multiple Sclerosis
- Being tested
- Stem Cell Transplanataion
- Keywords
- Demyelination, Inflammation, Immunosuppression, Autoimmunity, Bone Marrow, Multiple Sclerosis
- Medical subject headings
- Multiple Sclerosis, Demyelinating Diseases, Inflammation, Autoimmune Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Stem Cell TransplanataionProcedure or surgery
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Jun 2006 (estimated)
- Study start1 May 2002
- Primary completion4 May 2011
- Study completion4 May 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Multiple SclerosisStudies of the same condition, open and under way.
- More trials run by National Institute of Neurological Disorders and Stroke (NINDS)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Enrolment
- 34 participants (estimated)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00342134
- Sponsor's protocol ID
- 999902196
- Other IDs
- 02-N-N196
- Status last verified
- 4 May 2011
- First submitted
- 19 Jun 2006
- Last updated
- 2 Jul 2017
- Results posted
- No
Publications
Acha-Orbea H, Mitchell DJ, Timmermann L, Wraith DC, Tausch GS, Waldor MK, Zamvil SS, McDevitt HO, Steinman L. Limited heterogeneity of T cell receptors from lymphocytes mediating autoimmune encephalomyelitis allows specific immune intervention. Cell. 1988 Jul 15;54(2):263-73. doi: 10.1016/0092-8674(88)90558-2.
PubMed 2455603Bielekova B, Muraro PA, Golestaneh L, Pascal J, McFarland HF, Martin R. Preferential expansion of autoreactive T lymphocytes from the memory T-cell pool by IL-7. J Neuroimmunol. 1999 Dec;100(1-2):115-23. doi: 10.1016/s0165-5728(99)00200-3.
PubMed 10695722Burns FR, Li XB, Shen N, Offner H, Chou YK, Vandenbark AA, Heber-Katz E. Both rat and mouse T cell receptors specific for the encephalitogenic determinant of myelin basic protein use similar V alpha and V beta chain genes even though the major histocompatibility complex and encephalitogenic determinants being recognized are different. J Exp Med. 1989 Jan 1;169(1):27-39. doi: 10.1084/jem.169.1.27.
PubMed 2462609
Study at a glance
From the registry record, last updated by the sponsor on 2 Jul 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Immunological Mechanisms of Immune Ablation and Autologous Hematopoietic Stem Cell Transplantation in Secondary Progressive Multiple Sclerosis
- ClinicalTrials.gov ID
- NCT00342134
- Acronym / sponsor ID
- 999902196
- Conditions
- Multiple Sclerosis
- Keywords
- Demyelination, Inflammation, Immunosuppression, Autoimmunity, Bone Marrow, Multiple Sclerosis
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 34 participants (estimated)
- Lead sponsor
- National Institute of Neurological Disorders and Stroke (NINDS)US National Institutes of Health
- Study start
- 1 May 2002
- Primary completion
- 4 May 2011 (actual)
- Study completion
- 4 May 2011 (actual)
- First posted
- 21 Jun 2006 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Our goal is the elucidation of the mechanisms of action of autologous hematopoietic stem cell transplant (HSCT) and immunoablation by high-dose cyclophosphamide in multiple sclerosis (MS).
The molecular pathogenesis of multiple sclerosis is poorly understood although T-cell mediated immune destruction of myelin is thought to be an important element. We hypothesize, and the results of previous studies suggest, that radical immuno-ablation characterized by a profound T cell depletion can arrest the progression of disease. Patients with MS with poor prognosis based on the rate of progression and refractoriness to approved treatments (interferon-beta, glatiramer acetate) will be enrolled in clinical trials at the collaborating institution (NWU-Dr. R. Burt; Dr. D Kerr, JHU) and will receive either immune ablation with cyclophosphamide and the antibody Campath-1 followed by reconstitution with autologous peripheral blood stem cells, a procedure similar to autologous bone marrow transplantation, or high-dose cyclophosphamide treatment without stem cell rescue. While the overall treatment-related mortality worldwide is approximately 10%, the collaborating institution and investigators have an outstanding safety record in performing the procedure with no fatal adverse events after having transplanted more than 30 transplants with a previously more aggressive regimen than the one that is in use now. The underlying rationale for this treatment is that immuno-ablation could eliminate myelin-reactive T cells which, in disease-susceptible individuals, may have been activated by previous exposure to environmental agents or other acquired mechanisms of immune dysregulation.
In the proposed study we plan to address whether HSCT or immunoablation without stem cell rescue act beneficially in MS via the eradication of myelin-reactive T cells and reconstitution of a functional and non-autoimmune immune repertoire. To achieve this goal, we will compare peripheral blood T cell reactivities to myelin antigens before and after the treatment in 34 patients with MS. In parallel, to identify potential disease-mediating cells that do not recognize these myelin antigens, we will search for clonally expanded cells in the blood of MS patients before treatment employing molecular analysis of T cell receptor repertoire. Expanded T cell clones will be tracked during post-transplant follow-up of patients. If the eradication of certain clonotypes resulting from immuno-ablation correlates with disease remission, we will attempt to isolate these cells in culture from pre-treatment samples and determine their specificity using combinatorial peptide libraries. We would use the same approach in case of reappearance or new clonal expansions concomitant to disease relapses. We will combine these studies with a broader, unbiased approach that employs microarray technology to identify potential changes in gene expression profiles. This approach may also lead to the identification of novel therapeutic targets for pharmacological treatment.
Detailed description
Our goal is the elucidation of the mechanisms of action of autologous hematopoietic stem cell transplant (HSCT) and immunoablation by high-dose cyclophosphamide in multiple sclerosis (MS).
The molecular pathogenesis of multiple sclerosis is poorly understood although T-cell mediated immune destruction of myelin is thought to be an important element. We hypothesize, and the results of previous studies suggest, that radical immuno-ablation characterized by a profound T cell depletion can arrest the progression of disease. Patients with MS with poor prognosis based on the rate of progression and refractoriness to approved treatments (interferon-beta, glatiramer acetate) will be enrolled in clinical trials at the collaborating institution (NWU-Dr. R. Burt; Dr. D Kerr, JHU) and will receive either immune ablation with cyclophosphamide and the antibody Campath-1 followed by reconstitution with autologous peripheral blood stem cells, a procedure similar to autologous bone marrow transplantation, or high-dose cyclophosphamide treatment without stem cell rescue. While the overall treatment-related mortality worldwide is approximately 10%, the collaborating institution and investigators have an outstanding safety record in performing the procedure with no fatal adverse events after having transplanted more than 30 transplants with a previously more aggressive regimen than the one that is in use now. The underlying rationale for this treatment is that immuno-ablation could eliminate myelin-reactive T cells which, in disease-susceptible individuals, may have been activated by previous exposure to environmental agents or other acquired mechanisms of immune dysregulation.
In the proposed study we plan to address whether HSCT or immunoablation without stem cell rescue act beneficially in MS via the eradication of myelin-reactive T cells and reconstitution of a functional and non-autoimmune immune repertoire. To achieve this goal, we will compare peripheral blood T cell reactivities to myelin antigens before and after the treatment in 34 patients with MS. In parallel, to identify potential disease-mediating cells that do not recognize these myelin antigens, we will search for clonally expanded cells in the blood of MS patients before treatment employing molecular analysis of T cell receptor repertoire. Expanded T cell clones will be tracked during post-transplant follow-up of patients. If the eradication of certain clonotypes resulting from immuno-ablation correlates with disease remission, we will attempt to isolate these cells in culture from pre-treatment samples and determine their specificity using combinatorial peptide libraries. We would use the same approach in case of reappearance or new clonal expansions concomitant to disease relapses. We will combine these studies with a broader, unbiased approach that employs microarray technology to identify potential changes in gene expression profiles. This approach may also lead to the identification of novel therapeutic targets for pharmacological treatment.
Study design
- Primary purpose
- Treatment
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- Males and females between the ages of 18 and 70 years, inclusive.
- Diagnosis of clinically definite MS according to the McDonald Criteria.
- Must have been on conventional immunomodulatory treatment (interferon beta or glatiramer acetate for at least 3 months OR have not tolerated conventional treatment OR have refused to start conventional treatment).
- Two or more total gadolinium enhancing lesions on each of two pretreatment MRI scans at screening and enrollment OR one large enhancing lesion measuring at least 1 cm refractory treatment with IV steroids on each of the two pre-treatment scans.
- Subject must have EDSS ranging from 1.5 to 6.5.
Key exclusion criteria (9 listed)
- Any risk of pregnancy - ALL female patients must have an effective means of birth control or be infertile due to hysterectomy, fallopian tube surgery, or premature menopause.
- Cardiac ejection fraction of less than 45 percent.
- Serum creatinine greater than 2.0.
- Patients who are pre-terminal or moribund.
- Bilirubin greater than 2.0, transaminases greater than 2 times normal.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Stem Cell Transplanataion | Procedure or surgery | – |
Primary outcome
Not reported in the source record.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Jul 2017.
- Background: PubMed 2455603Acha-Orbea H, Mitchell DJ, Timmermann L, Wraith DC, Tausch GS, Waldor MK, Zamvil SS, McDevitt HO, Steinman L. Limited heterogeneity of T cell receptors from lymphocytes mediating autoimmune encephalomyelitis allows specific immune intervention. Cell. 1988 Jul 15;54(2):263-73. doi: 10.1016/0092-8674(88)90558-2.
- Background: PubMed 10695722Bielekova B, Muraro PA, Golestaneh L, Pascal J, McFarland HF, Martin R. Preferential expansion of autoreactive T lymphocytes from the memory T-cell pool by IL-7. J Neuroimmunol. 1999 Dec;100(1-2):115-23. doi: 10.1016/s0165-5728(99)00200-3.
- Background: PubMed 2462609Burns FR, Li XB, Shen N, Offner H, Chou YK, Vandenbark AA, Heber-Katz E. Both rat and mouse T cell receptors specific for the encephalitogenic determinant of myelin basic protein use similar V alpha and V beta chain genes even though the major histocompatibility complex and encephalitogenic determinants being recognized are different. J Exp Med. 1989 Jan 1;169(1):27-39. doi: 10.1084/jem.169.1.27.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Stem Cell Transplanataion in people with Multiple Sclerosis, run by National Institute of Neurological Disorders and Stroke (NINDS) at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Jul 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00342134, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Jul 2017.