Multiple SclerosisPhase 2NCT00273364
Stem Cell Therapy for Patients With Multiple Sclerosis Failing Alternate Approved Therapy- A Randomized Study
A Phase 2 study testing Hematopoietic Stem Cell Therapy and Standard treatment with a conventional drug in people with Multiple Sclerosis, run by Northwestern University at 1 site in United States.
Trial summary
Multiple sclerosis (MS) is at onset an immune-mediated demyelinating disease. In most cases, it starts as a relapsing-remitting disease with distinct attacks and no symptoms between flares. Read more about this study
- Who is it for?
- Ages 18 to 55 years
- Conditions the study is for
- Multiple Sclerosis
- What is being tested?
- Hematopoietic Stem Cell Therapy and Standard treatment with a conventional drug
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 110 participants
- Where
- 1 siteUnited States
- Study dates
- 16 Nov 2005to 30 Aug 2019
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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 55 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- Age between18-55, inclusive.
- Diagnosis of MS using revised McDonald criteria of clinically definite MS (Appendix I).
- An EDSS score of 2.0 to 6.0 (Appendix II).
- Inflammatory disease despite treatment with standard disease modifying therapy including at least 6 months of interferon or copaxone. Inflammatory disease is defined based on both MRI (gadolinium enhancing lesions) and clinical activity (acute relapses *treated with IV or oral high dose corticosteroids and prescribed by a neurologist). Minimum disease activity required for failure is defined as: a) two or more *steroid treated clinical relapses with documented new objective signs on neurological examination documented by a neurologist within the year prior to the study, or b) one *steroid treated clinical relapse within the year prior to study and evidence on MRI of active inflammation (i.e., gadolinium enhancement) within the last 12 months on an occasion separate from the clinical relapse (3 months before or after the clinical relapse).
- A steroid treated relapse will include a relapse that was severe enough to justify treatment but due to patient intolerance of steroids, or a history of non-response to steroids, they were offered but not used.
Who cannot join
- Any illness that in the opinion of the investigators would jeopardize the ability of the patient to tolerate aggressive chemotherapy.
- Prior history of malignancy except localized basal cell, squamous skin cancer or carcinoma in situ of the cervix. Other malignancies for which the patient is judged to be cured, such as head and neck cancer, or breast cancer will be considered on an individual basis.
- Positive pregnancy test
- Inability or unwillingness to pursue effective means of birth control from the time of evaluation for eligibility until 6 months posttransplant (if on transplant) or until appropriate for non-transplant treatment (if on control arm). Effective birth control is defined as 1) abstinence defined as refraining from all acts of vaginal intercourse; 2) consistent use of birth control pills; 3) injectable birth control methods (Depo-provera, Norplant); 4) tubal sterilization or male partner who has undergone vasectomy; 5) placement of an intrauterine device (IUD); or 6) use, with every act of intercourse, of diaphragm with contraceptive jelly and/or condoms with contraceptive foam.
- Failure to willingly accept or comprehend irreversible sterility as a side effect of therapy
- Forced expiratory volume at one second (FEV1) / forced vital capacity (FVC) < 60% of predicted after bronchodilator therapy (if necessary)
Show all 25Show fewer
- Diffusing capacity of lung for carbon monoxide (DLCO) < 50% of predicted (for the transplant arm)
- Resting left ventricular ejection fraction (LVEF) < 50 %
- Bilirubin > 2.0 mg/dl
- Serum creatinine > 2.0 mg/dl
- Known hypersensitivity to mouse, rabbit, or E. Coli derived proteins, or to iron compounds/medications
- Presence of metallic objects implanted in the body that would preclude the ability of the patient to safely have MRI exams
- Diagnosis of primary progressive MS
- Diagnosis of secondary progressive MS
- Platelet count < 100,000/ul, white blood cell count (WBC) < 1,500 cells/mm3
- Psychiatric illness, mental deficiency or cognitive dysfunction making compliance with treatment or informed consent impossible
- Active infection except asymptomatic bacteriuria
- Use of natalizumab (Tysabri) within the previous 6 months
- Use of fingolimod (Gilenya) within the previous 3 months
- Use of teriflunomide (Aubagio) within the previous 2 years unless cleared from the body (plasma concentration < 0.02mcg/ml) following elimination from the body with cholestyramine 8g three times a day for 11 days
- Prior treatment with CAMPATH (alemtuzumab)
- Prior treatment with mitoxantrone
- Any hereditary neurological disease such as Charcot-Marie-Tooth disease (CMT) or Spinocerebellar ataxia (SCA) are contraindications
- Use of tecfidera within the previous 3 months
- For patients who clearly have inflammatory disease, an exception can be made if agreed upon by study PI and at least two study neurologists.
Trial locations and contacts
1 site in 1 country.
United States1 site
Northwestern University, Feinberg School of Medicine
Chicago, Illinois, 60611
About this study
Official title: Hematopoietic Stem Cell Therapy for Patients With Inflammatory Multiple Sclerosis Failing Alternate Approved Therapy: A Randomized Study
Multiple sclerosis (MS) is at onset an immune-mediated demyelinating disease. In most cases, it starts as a relapsing-remitting disease with distinct attacks and no symptoms between flares. Over years or decades, virtually all cases transition into a progressive disease in which insidious and slow neurologic deterioration occurs with or without acute flares. Relapsing-remitting disease is often responsive to immune suppressive or modulating therapies, while immune based therapies are generally ineffective in patients with a progressive clinical course. This clinical course and response to immune suppression, as well as neuropathology and neuroimaging studies, suggest that disease progression is associated with axonal atrophy. Disability correlates better with measures of axonal atrophy than immune mediated demyelination. Therefore, immune based therapies, in order to be effective, need to be started early in the disease course while MS is predominately an immune-mediated and inflammatory disease. While current immune based therapies delay disability, no intervention has been proven to prevent progressive disability. We propose, as a randomized study, autologous unmanipulated PBSCT using a conditioning regimen of cyclophosphamide and rabbit antithymocyte globulin (rATG) versus FDA approved standard of care (i.e. interferon, glatiramer acetate, mitoxantrone, natalizumab, fingolimod, or tecfidera) in patients with inflammatory (relapsing) MS despite treatment with alternate approved therapy.
Read the detailed description
To assess the efficacy of autologous PBSCT versus FDA approved standard of care ( i.e. interferon, glatiramer acetate, mitoxantrone, natalizumab, fingolimod, or tecfidera) for inflammatory multiple sclerosis (MS) failing failing alternate approved therapy. The endpoints to be considered in this study are:
2.1 Primary Endpoint:
Disease progression, defined as a 1 point increase in the Expanded Disability Status Scale (EDSS) on consecutive evaluations at least 6 months apart and not due to a non-MS disease process. Patients will be followed for 5 years after randomization.
- Conditions
- Multiple Sclerosis
- Being tested
- Hematopoietic Stem Cell Therapy, Standard treatment with a conventional drug
- Keywords
- stem cell, autoimmune disease, multiple sclerosis
- Medical subject headings
- Multiple Sclerosis, Autoimmune Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Hematopoietic Stem Cell TherapyProcedure or surgery
Also called stem cell infusion
After mobilization and harvest of stem cells, stem cells will be infused following conditioning regimen
Standard treatment with a conventional drugDrug
Also called standard of care
Standard treatment with a conventional drug is the treatment with one of the following drugs: Avonex (interferon beta 1a), Betaseron (interferon beta 1b), Copaxone (glatiramer acetate), Aubagio (teriflunomide), Tysabri (natalizumab), or Gilenya (fingolimod)
| Study group | Role | What they receive |
|---|---|---|
| Hematopoietic Stem Cell Transplantation | Experimental | Hematopoietic Stem Cell Therapy will be performed as follows: Autologous stem cells will be infused after conditioning with Cyclophosphamide and rATG Receives: Procedure: Hematopoietic Stem Cell Therapy |
| Standard therapy for MS | Active comparator | Standard treatment with a conventional drug is the treatment with one of the following drugs: Avonex (interferon beta 1a), Betaseron (interferon beta 1b), Copaxone (glatiramer acetate), Aubagio (teriflunomide), Tysabri (natalizumab), Gilenya (fingolimod) or Dimethyl fumarate (Tecfidera or BG-12) Receives: Drug: Standard treatment with a conventional drug |
What is being measured
The primary outcome is the main question the study is designed to answer.
Expanded Disability Status Scale (EDSS) Improvement
The EDSS scale ranges from 0 to 10 in 0.5 increments that represent higher levels of disability. Improvement in EDSS is defined by both a 0.5 or 1.0 points sustained for more than 6 months.
Measured: Pre Treatment, 6 and 12 months Post Treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Jan 2006 (estimated)
- Study start16 Nov 2005
- Primary completion5 Jan 2017
- Study completion30 Aug 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)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 Northwestern UniversityThe 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
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 110 participants (actual)
Sponsor and investigators
- Lead sponsor
- Northwestern University
- Sponsor type
- University, hospital or other
- Collaborators
- Uppsala University, Sheffield Teaching Hospitals NHS Foundation Trust, University of Sao Paulo
- Responsible party
- Principal investigator, Richard Burt, MD, Northwestern University
- Investigators
- Richard Burt, MD, Principal investigator, Northwestern University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00273364
- Sponsor's protocol ID
- DI MS.Randomized2004
- Status last verified
- Apr 2019
- First submitted
- 5 Jan 2006
- Last updated
- 12 Aug 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Burt RK, Balabanov R, Burman J, Sharrack B, Snowden JA, Oliveira MC, Fagius J, Rose J, Nelson F, Barreira AA, Carlson K, Han X, Moraes D, Morgan A, Quigley K, Yaung K, Buckley R, Alldredge C, Clendenan A, Calvario MA, Henry J, Jovanovic B, Helenowski IB. Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial. JAMA. 2019 Jan 15;321(2):165-174. doi: 10.1001/jama.2018.18743.
PubMed 30644983Burman J, Fransson M, Totterman TH, Fagius J, Mangsbo SM, Loskog AS. T-cell responses after haematopoietic stem cell transplantation for aggressive relapsing-remitting multiple sclerosis. Immunology. 2013 Oct;140(2):211-9. doi: 10.1111/imm.12129.
PubMed 23721329
Study at a glance
From the registry record, last updated by the sponsor on 12 Aug 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Hematopoietic Stem Cell Therapy for Patients With Inflammatory Multiple Sclerosis Failing Alternate Approved Therapy: A Randomized Study
- ClinicalTrials.gov ID
- NCT00273364
- Acronym / sponsor ID
- DI MS.Randomized2004
- Conditions
- Multiple Sclerosis
- Keywords
- stem cell, autoimmune disease, multiple sclerosis
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 110 participants (actual)
- Lead sponsor
- Northwestern UniversityUniversity, hospital or other
- Collaborators
- Uppsala University, Sheffield Teaching Hospitals NHS Foundation Trust, University of Sao Paulo
- Study start
- 16 Nov 2005 (actual)
- Primary completion
- 5 Jan 2017 (actual)
- Study completion
- 30 Aug 2019 (actual)
- First posted
- 9 Jan 2006 (estimated)
- Results
- Posted 12 Aug 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Multiple sclerosis (MS) is at onset an immune-mediated demyelinating disease. In most cases, it starts as a relapsing-remitting disease with distinct attacks and no symptoms between flares. Over years or decades, virtually all cases transition into a progressive disease in which insidious and slow neurologic deterioration occurs with or without acute flares. Relapsing-remitting disease is often responsive to immune suppressive or modulating therapies, while immune based therapies are generally ineffective in patients with a progressive clinical course. This clinical course and response to immune suppression, as well as neuropathology and neuroimaging studies, suggest that disease progression is associated with axonal atrophy. Disability correlates better with measures of axonal atrophy than immune mediated demyelination. Therefore, immune based therapies, in order to be effective, need to be started early in the disease course while MS is predominately an immune-mediated and inflammatory disease. While current immune based therapies delay disability, no intervention has been proven to prevent progressive disability. We propose, as a randomized study, autologous unmanipulated PBSCT using a conditioning regimen of cyclophosphamide and rabbit antithymocyte globulin (rATG) versus FDA approved standard of care (i.e. interferon, glatiramer acetate, mitoxantrone, natalizumab, fingolimod, or tecfidera) in patients with inflammatory (relapsing) MS despite treatment with alternate approved therapy.
Detailed description
To assess the efficacy of autologous PBSCT versus FDA approved standard of care ( i.e. interferon, glatiramer acetate, mitoxantrone, natalizumab, fingolimod, or tecfidera) for inflammatory multiple sclerosis (MS) failing failing alternate approved therapy. The endpoints to be considered in this study are:
2.1 Primary Endpoint:
Disease progression, defined as a 1 point increase in the Expanded Disability Status Scale (EDSS) on consecutive evaluations at least 6 months apart and not due to a non-MS disease process. Patients will be followed for 5 years after randomization.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Hematopoietic Stem Cell Transplantation | Experimental | Procedure: Hematopoietic Stem Cell TherapyHematopoietic Stem Cell Therapy will be performed as follows: Autologous stem cells will be infused after conditioning with Cyclophosphamide and rATG |
| Standard therapy for MS | Active comparator | Drug: Standard treatment with a conventional drugStandard treatment with a conventional drug is the treatment with one of the following drugs: Avonex (interferon beta 1a), Betaseron (interferon beta 1b), Copaxone (glatiramer acetate), Aubagio (teriflunomide), Tysabri (natalizumab), Gilenya (fingolimod) or Dimethyl fumarate (Tecfidera or BG-12) |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- Age between18-55, inclusive.
- Diagnosis of MS using revised McDonald criteria of clinically definite MS (Appendix I).
- An EDSS score of 2.0 to 6.0 (Appendix II).
- Inflammatory disease despite treatment with standard disease modifying therapy including at least 6 months of interferon or copaxone. Inflammatory disease is defined based on both MRI (gadolinium enhancing lesions) and clinical activity (acute relapses *treated with IV or oral high dose corticosteroids and prescribed by a neurologist). Minimum disease activity required for failure is defined as: a) two or more *steroid treated clinical relapses with documented new objective signs on neurological examination documented by a neurologist within the year prior to the study, or b) one *steroid treated clinical relapse within the year prior to study and evidence on MRI of active inflammation (i.e., gadolinium enhancement) within the last 12 months on an occasion separate from the clinical relapse (3 months before or after the clinical relapse).
Key exclusion criteria (25 listed)
- Any illness that in the opinion of the investigators would jeopardize the ability of the patient to tolerate aggressive chemotherapy.
- Prior history of malignancy except localized basal cell, squamous skin cancer or carcinoma in situ of the cervix. Other malignancies for which the patient is judged to be cured, such as head and neck cancer, or breast cancer will be considered on an individual basis.
- Positive pregnancy test
- Inability or unwillingness to pursue effective means of birth control from the time of evaluation for eligibility until 6 months posttransplant (if on transplant) or until appropriate for non-transplant treatment (if on control arm). Effective birth control is defined as 1) abstinence defined as refraining from all acts of vaginal intercourse; 2) consistent use of birth control pills; 3) injectable birth control methods (Depo-provera, Norplant); 4) tubal sterilization or male partner who has undergone vasectomy; 5) placement of an intrauterine device (IUD); or 6) use, with every act of intercourse, of diaphragm with contraceptive jelly and/or condoms with contraceptive foam.
- Failure to willingly accept or comprehend irreversible sterility as a side effect of therapy
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 |
|---|---|---|
| Hematopoietic Stem Cell TherapyAlso: stem cell infusionAfter mobilization and harvest of stem cells, stem cells will be infused following conditioning regimen | Procedure or surgery | Hematopoietic Stem Cell Transplantation |
| Standard treatment with a conventional drugAlso: standard of careStandard treatment with a conventional drug is the treatment with one of the following drugs: Avonex (interferon beta 1a), Betaseron (interferon beta 1b), Copaxone (glatiramer acetate), Aubagio (teriflunomide), Tysabri (natalizumab), or Gilenya (fingolimod) | Drug | Standard therapy for MS |
Primary outcome
Expanded Disability Status Scale (EDSS) Improvement
Time frame: Pre Treatment, 6 and 12 months Post Treatment
The EDSS scale ranges from 0 to 10 in 0.5 increments that represent higher levels of disability. Improvement in EDSS is defined by both a 0.5 or 1.0 points sustained for more than 6 months.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Aug 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 30644983Burt RK, Balabanov R, Burman J, Sharrack B, Snowden JA, Oliveira MC, Fagius J, Rose J, Nelson F, Barreira AA, Carlson K, Han X, Moraes D, Morgan A, Quigley K, Yaung K, Buckley R, Alldredge C, Clendenan A, Calvario MA, Henry J, Jovanovic B, Helenowski IB. Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial. JAMA. 2019 Jan 15;321(2):165-174. doi: 10.1001/jama.2018.18743.
- Derived from this study: PubMed 23721329Burman J, Fransson M, Totterman TH, Fagius J, Mangsbo SM, Loskog AS. T-cell responses after haematopoietic stem cell transplantation for aggressive relapsing-remitting multiple sclerosis. Immunology. 2013 Oct;140(2):211-9. doi: 10.1111/imm.12129.
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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.
Richard Burt, MD principal investigator
Northwestern University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Hematopoietic Stem Cell Therapy and Standard treatment with a conventional drug in people with Multiple Sclerosis, run by Northwestern University at 1 site 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 5 inclusion and 25 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 12 Aug 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site 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?
Yes. Results are posted in the registry (first posted 12 Aug 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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.
What does the primary outcome measure?
Expanded Disability Status Scale (EDSS) Improvement (time frame: Pre Treatment, 6 and 12 months Post Treatment). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00273364, which also lists 2 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 12 Aug 2020.