High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT MS) Study

Study Overview
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Brief Summary
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The purpose of this study is to determine the effectiveness of a new treatment for multiple sclerosis (MS), a serious disease in which the immune system attacks the brain and spinal cord. MS can be progressive and severe and lead to significant disability. The study treatment involves the use of high-dose chemotherapeutic drugs to suppress the immune system. The participant's own (autologous) blood-forming (hematopoietic, CD34+) stem cells are collected before the chemotherapy is given, and then transplanted back into the body following treatment. Transplantation of autologous hematopoietic stem cells is required to prevent very prolonged periods of low blood cell counts after the high-dose chemotherapy.

Detailed Description
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MS is a chronic autoimmune disease of the central nervous system in which myelin, the protective coat that surrounds nerve cells, is damaged or destroyed by autoimmune T cells and macrophages, leading to an eventual loss of neurologic function. In a pilot study in Europe using high-dose chemotherapy, it was observed that 18 of 19 MS patients stabilized or improved clinically, and only one patient showed a new lesion on magnetic resonance imaging (MRI) of the brain at 4.5 years after treatment. Improvement was seen in quality-of-life assessments. In ITN033AI, high-dose chemotherapy with autologous CD34-selected hematopoietic cell transplantation will be given to confirm the results from the pilot study and to offer therapy to patients with early MS and a poor prognosis. Research studies will be performed in addition to clinical assessments to better understand the effect of the treatment on the activity of MS. High-dose chemotherapy will be used to deplete autoreactive immune cells. These regimens also deplete the bone marrow, the source of blood-forming CD34+ stem cells which causes very low blood counts. Therefore, the participant's autologous CD34+ hematopoietic stem cells will be collected before high dose immunosuppressive therapy is given and then returned as a transplant post-chemotherapy. Patients will be followed closely after the autologous transplantation since they will be at risk for infections after treatment. At the beginning of the study, participants will undergo a number of screening and baseline procedures, including a physical exam, blood collection, MS-confirming neurology exams and questionnaires, and MRI procedures. Participants will be given prednisone and granulocyte-colony stimulating factor (G-CSF) to mobilize CD34+ hematopoietic stem cells from the bone marrow into the peripheral blood. When the peripheral blood CD34+ cell count reaches 20,000 cells/ml or greater, these cells will be collected by leukapheresis. In this process, a catheter is placed into a large blood vessel, peripheral blood is withdrawn, and a high speed sedimentation (leukapheresis) device is used to separate and retain the cells required for autologous transplantation. Other blood cells are then returned to the participant's body. In the laboratory, the CD34+ hematopoietic stem cell graft will be selected and prepared from the leukapheresis collection, and stored until needed for transplant. Seven or more days following the collection of their autologous graft, participants will be hospitalized and receive high-dose chemotherapy consisting of carmustine, etoposide, cytarabine, and melphalan (BEAM) and thymoglobulin. This is followed by transplantation of the autologous hematopoietic cell graft. Participants will remain in the hospital for observation during recovery of their peripheral blood cell counts, as described in the protocol. Participants will receive G-CSF and blood transfusions, if needed, and will be monitored for infections. Following discharge from the hospital, eight study visits will occur over sixty months (five years). During these visits, participants will undergo blood and urine collection, MRI studies, leukapheresis, and MS neurology exams and will complete questionnaires.

Official Title
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A Phase II Study of High-Dose Immunosuppressive Therapy Using Carmustine, Etoposide, Cytarabine, Melphalan, Thymoglobulin and Autologous CD34+ Hematopoietic Stem Cell Transplant for the Treatment of Poor Prognosis Multiple Sclerosis

Conditions
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Relapsing-Remitting Multiple Sclerosis

Intervention / Treatment
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* Drug: Granulocyte-colony stimulating factor (G-CSF) and prednisone
* Drug: Carmustine, etoposide, cytarabine, and melphalan (BEAM)
* Procedure: Autologous hematopoietic stem cell transplant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of relapsing-remitting or progressive-relapsing multiple sclerosis for less than 15 years using McDonald Criteria. More information on this criterion can be found in the protocol Score between 3.0 and 5.5 on the Expanded Disability Status Scale (EDSS) T2 abnormalities on brain MRI consistent with MS Two or more relapses in 18 months time on interferon (IFN), glatiramer acetate (GA), natalizumab or cytotoxic therapy with EDSS increase of 1.0 or greater for participants with EDSS at screening of 3.0 to 3.5 (0.5 or greater for participants with EDSS at screening of 4.0 to 5.5) sustained at least 4 weeks after at least one of these relapses OR one relapse on IFN, GA, natalizumab or cytotoxic therapy with EDSS increase of 1.5 or greater (1.0 for subjects with EDSS at screening of 5.5) sustained at least 4 weeks, together with MRI changes consistent with poor prognosis. More information on this criterion can be found in the protocol. On IFN or GA for at least 6 months before the relapses occur that are counted to satisfy previous inclusion criterion OR have received adequate doses of natalizumab or cytotoxic therapy on a treatment schedule before the relapses occur that are counted to satisfy previous inclusion criterion Approval by an MS Review Panel to participate in the study. More information on this criterion can be found in the protocol In good clinical condition with adequate organ function and without coexisting medical problems that would increase the risk to the participant Willing to use acceptable methods of contraception Willing and able to comply with all study requirements and Willing to accept and comprehend irreversible sterility as side effect of therapy. Exclusion Criteria: Primary progressive MS Secondary progressive MS without relapses (i.e., progression without exacerbations or relapses) for 12 or more months Neuromyelitis optica, a disease similar to MS Initiation of new immunosuppressant treatment after the participant becomes eligible for the protocol or continuance of immunosuppressant drugs after the participant is screened for the protocol. Treatment with IFN, GA, or corticosteroids is permitted after the participant becomes eligible for the protocol. Lapse of greater than 6 months between the time a participant is eligible for the protocol and initiation of protocol treatment except when judged acceptable by the MS Review Panel Prior treatment with investigational immunosuppressive agents within 3 months of study eligibility Positive baseline plasma and CSF testing for JC virus or a brain MRI that has changes consistent with a diagnosis of progressive multifocal encephalopathy (PML) History of cytopenia consistent with the diagnosis of myelodysplastic syndrome (MDS) Active hepatitis B or C infection, cirrhosis, or HIV infection Uncontrolled diabetes mellitus Uncontrolled viral, fungal, or bacterial infection. Patients with asymptomatic bacteriuria are not excluded Any illness that would jeopardize the ability to tolerate aggressive chemotherapy Prior history of malignancy, except localized basal cell or squamous skin cancer. Other malignancies for which the subject is judged cured by the administered therapy will be considered on an individual basis. Hypersensitivity to mouse, rabbit, or Escherichia coli-derived proteins or to iron compounds/medications Metallic objects implanted in the body that would affect MRI exams Psychiatric illness, mental deficiency, or cognitive dysfunction or Pregnancy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MS Treatment<br>Autologous peripheral blood stem cell grafts were CD34+ selected; the participants then received high-dose treatment with carmustine, etoposide, cytarabine, and melphalan as well as rabbit antithymocyte globulin before autologous HCT. | Drug: Granulocyte-colony stimulating factor (G-CSF) and prednisone<br>* Growth factor regimen; occurs at study entry<br>Drug: Carmustine, etoposide, cytarabine, and melphalan (BEAM)<br>* High-dose chemotherapy; occurs seven or more days following collection of autologous graft<br>Procedure: Autologous hematopoietic stem cell transplant<br>* Occurs after growth factor regimen and collection of autologous graft<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-Free Survival Probability During the 5 Years After Transplant | Event-free survival (EFS) is survival without death or disease activity from any one of the following criteria: 1) loss of neurological function, defined as a change in pretransplant Extended Disability Status Scale (EDSS) of > 0.5. 2) Relapse, defined as the development of a new neurological sign and corresponding symptom, or worsening of an existing neurological sign and symptom, localized to central nervous system white matter, resulting in neurological deficit/disability, and lasting over 48 hours. 3) New lesions on magnetic resonance imaging (MRI), defined as presence of 2 or more independent multiple sclerosis brain lesions detected on MRI 1 year or more after stem cell transplant. Kaplan-Meier estimates of survival probability, with 90% confidence interval based on Greenwood's formula for standard error. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-Free Survival Probability During the 3 Years After Transplant | Event-free survival (EFS) is survival without death or disease activity from any one of the following criteria: 1) loss of neurological function, defined as a change in pretransplant Extended Disability Status Scale (EDSS) of > 0.5. 2) Relapse, defined as the development of a new neurological sign and corresponding symptom, or worsening of an existing neurological sign and symptom, localized to central nervous system white matter, resulting in neurological deficit/disability, and lasting over 48 hours. 3) New lesions on magnetic resonance imaging (MRI), defined as presence of 2 or more independent multiple sclerosis brain lesions detected on MRI 1 year or more after stem cell transplant. Kaplan-Meier estimates of survival probability, with 90% confidence interval based on Greenwood's formula for standard error. | 3 years | 
| Survival From Treatment-Related Mortality | The probability that a participant did not experienced a treatment-related death estimated at 1, 2, 3, 4, and 5 years following transplant via the Kaplan-Meier Method. Greenwood's formula for standard error was used to calculate 90% confidence intervals. Participants that did not experience a treatment-related death were censored at the time of last follow-up. A treatment-related death was defined as death that occurred at any time after study entry and that was possibly, probably, or definitely related to the cellular product or possibly, probably, or definitely related to mobilization of autologous peripheral blood hematopoietic progenitor cells with G-CSF and prednisone or to the high-dose immunosuppressive therapy. There were no treatment-related mortality events in the study. | From study entry to death, loss to follow-up, or the end of the study, whichever came first, up to 6 years | 
| Overall Survival | The probability that a participant did not experienced a death estimated at 1, 2, 3, 4, and 5 years following transplant via the Kaplan-Meier Method. Greenwood's formula for standard error was used to calculate 90% confidence intervals. Participants that did not die were censored at the time of last follow-up. | From study entry to death, loss to follow-up, or the end of the study, whichever came first, up to 6 years | 
| Survival From MS-Related Mortality | The probability that a participant did not experienced a MS-related death estimated at 1, 2, 3, 4, and 5 years following transplant via the Kaplan-Meier Method. Greenwood's formula for standard error was used to calculate 90% confidence intervals. Participants that did not experience a MS-related death were censored at the time of last follow-up. A MS-related death was defined as death that occurred at any time after study entry and that was possibly, probably, or definitely related to disease progression. | From study entry to death, loss to follow-up, or the end of the study, whichever came first, up to 6 years | 
| Percent of Participants Who Experienced All-Cause Morbidity | Morbidity is the occurrence of NCI Common Terminology Criteria for Adverse Events (CTCAE) v3.0 adverse event grade 3 or higher. | From the time of enrollment until completion of the 5-year follow-up, an average of 6 years. | 
| Percent of Participants Who Experienced All-Cause Morbidity Within 12 Months of Post-HCT | Morbidity is the occurrence of NCI Common Terminology Criteria for Adverse Events (CTCAE) v3.0 adverse event grade 3 or higher. | From the time of Autologous CD34+ Hematopoietic Stem Cell Transplant (HCT) to 1 year after HCT. | 
| Time to Neutrophil Engraftment | Neutrophil engraftment, or neutrophil count recovery, is defined as an Absolute Neutrophil Count (ANC) > 500/ μL for 2 consecutive measurements on different days. Normal range is 1500 to 8000/μL. Reference: http://www.medicinenet.com | From time of graft infusion to time of engraftment, up to 6 years | 
| Time to Platelet Engraftment | Platelet engraftment, or platelet count recovery, is defined as Platelets > 20,000/μL for two consecutive measurements on different days with no platelet transfusions in the preceding 7 days. Normal range is 150,000-450,000/μL. Reference: http://www.hopkinsmedicine.org/heart_vascular_institute/clinical_services/centers_excellence/womens_cardiovascular_health_center/patient_information/health_topics/platelets.html. | From time of graft infusion to time of engraftment, up to 6 years | 
| Event-Free Survival Probability After Transplant | Event-free survival (EFS) is survival without death or disease activity from any one of the following criteria: 1) loss of neurological function, defined as a change in pretransplant Extended Disability Status Scale (EDSS) of > 0.5. 2) Relapse, defined as the development of a new neurological sign and corresponding symptom, or worsening of an existing neurological sign and symptom, localized to central nervous system white matter, resulting in neurological deficit/disability, and lasting over 48 hours. 3) New lesions on magnetic resonance imaging (MRI), defined as presence of 2 or more independent multiple sclerosis brain lesions detected on MRI 1 year or more after stem cell transplant. Kaplan-Meier estimates of survival probability, with 90% confidence intervals based on Greenwood's formula for standard error. | 1, 2, and 4 years after HCT | 
| MS Progression-Free Survival Probability After Transplant | MS progression is measured as number of days from transplant to first Kurtzke's Expanded Disability Status Scale (EDSS) increase of more than 0.5 relative to the baseline measurement. EDSS assesses disability in Multiple Sclerosis patients. Eight functional systems are evaluated: visual, brain stem, pyramidal, cerebellar, sensory, bowel and bladder, cerebral, and ambulation. The overall score ranges from 0 (normal neurological exam) to 10 (death due to MS). Kaplan-Meier estimates of survival probability, with 90% confidence intervals based on Greenwood's formula for standard error. | 1 to 5 years after HCT | 
| MRI Activity-Free Survival Probability After Transplant | MS disease activity is measured as days from transplant to first occurrence of >= 2 new MS lesions on Magnetic resonance imaging (MRI) relative to baseline. Kaplan-Meier estimates of survival probability, with 90% confidence intervals based on Greenwood's formula for standard error. | 1 to 5 years after HCT | 
| MS Relapse-Free Survival Probability After Transplant | MS clinical relapse is defined as the development of a new neurological sign and corresponding symptom, or worsening of an existing neurological sign and symptom, localized to central nervous system white matter, resulting in neurological deficit or disability, and lasting over 48 hours. Clinical relapse was determined by the participant's neurologist and was measured as days from transplant to new or worsening neurological symptom relative to baseline. Kaplan-Meier estimates of survival probability, with 90% confidence interval based on Greenwood's formula for standard error. | 1 to 5 years after HCT | 
| Disease-Modifying Therapy Survival Probability After Transplant | Treatment with disease-modifying therapy was measured by the number of days from transplant to the first treatment with an additional disease-modifying therapy. Examples of therapy include interferon beta-1a, glatiramer acetate, natalizumab, alemtuzumab, other immunosuppressive medications, or experimental therapies directed against MS activity. Kaplan-Meier estimates of survival probability, with 90% confidence interval based on Greenwood's formula for standard error. | 1 to 5 years after HCT | 
| Change From Baseline in Extended Disability Status Scale (EDSS) | Kurtzke's Expanded Disability Status Scale (EDSS) assesses disability in Multiple Sclerosis patients. Eight functional systems are evaluated: visual, brain stem, pyramidal, cerebellar, sensory, bowel and bladder, cerebral, and ambulation. The overall score ranges from 0 (normal neurological exam) to 10 (death due to MS). Change from baseline was computed as the value at the time point minus the baseline value. A negative value in change from baseline indicates an improvement and a positive value indicates worsening. A change of > 0.5 in EDSS was a treatment-failure criterion. | 6 months to 5 years after HCT | 
| Change From Baseline in Number of Gadolinium-Enhanced Lesions | Multiple sclerosis disease-related lesions were assessed by gadolinium-enhanced magnetic resonance imaging (MRI). Change from baseline was computed as the value at the time point minus the baseline value. A negative value in change from baseline indicates an improvement and a positive value indicates worsening. | 8 weeks to 5 years after HCT | 
| Number of New T2-Weighted Lesions From Baseline | A T2-weighted magnetic resonance imaging (MRI) scan was used to determine the number of new T2 lesions in the brain relative to Baseline. A value of 0 means that the participant didn't worsen. Values greater than 0 indicate an increase in disease activity from baseline. | 6 Months to 5 years after HCT | 
| Change From Baseline in T2-Weighted Lesion Volume | A T2-weighted magnetic resonance imaging (MRI) scan was used to assess the volume of T2 lesions in the brain. Change from baseline was computed as the value at the time point minus the baseline value. | 8 weeks to 5 years after HCT | 
| Change From Baseline in T1-Weighted Lesion Volume | A T1-weighted magnetic resonance imaging (MRI) scan was used to assess the volume of T1 lesions in the brain. Change from baseline was computed as the value at the time point minus the baseline value. | 8 weeks to 5 years after HCT | 
| Percent Change From Screening in Brain Volume | Magnetic resonance imaging (MRI) scan techniques measured ventricular volumes and grey and white matter brain volumes. Change from screening was computed as the value at the time point minus the screening value. | 8 weeks to 5 years after HCT | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hematopoietic stem cell transplantation, HCT- autologous hematopoietic cell transplant, HDIT-high-dose immunosuppressive therapy, BEAM -Carmustine (BCNU), Etoposide (VP-16), Cytarabine (ara-C), and Melphalan