Maximizing Outcome of Multiple Sclerosis Transplantation: "MOST" Trial

Northwestern University1 个研究点分布在 1 个国家目标入组 66 人开始时间: 2017年11月8日最近更新: 2021年1月11日

适应症

干预措施

试验速览

阶段: 3 期
状态: 终止
发起方: Northwestern University
入组人数: 66
试验地点: 1
主要终点: Efficacy - Rate of Disease Activity

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

Randomized study of autologous un-manipulated peripheral blood hematopoietic stem cell transplant (HSCT) comparing two regimens: (1) cyclophosphamide and rabbit anti-thymoglobulin (rATG) versus (2) cyclophosphamide, rATG, and Intravenous Immunoglobulin (IVIg).

详细描述

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 predominantly an immune-mediated and inflammatory disease. While current immune based therapies delay disability, no intervention has been proven to prevent progressive disability.The investigators propose a randomized study of autologous unmanipulated peripheral blood hematopoietic stem cell transplant (HSCT) comparing two different conditioning regimens: (1) cyclophosphamide and rabbit anti-thymoglobulin (rATG) versus (2) cyclophosphamide, rATG, and Intravenous Immunoglobulin (IVIg).

研究设计

研究类型: Interventional
分配方式: Randomized
干预模型: Parallel
主要目的: Treatment
盲法: None

入排标准

年龄范围: 18 Years 至 58 Years（Adult）
性别: All
接受健康志愿者: 否

入选标准

•Age between 18-58 years
•Diagnosis of MS using revised McDonald criteria of clinically definite MS (Appendix A)
•An EDSS score of 2.0 to 6.0 (Appendix B).
•An EDSS >6.0 may be included if still relapsing-remitting disease and at least two enhancing lesions on MRI within the last three months
•Inflammatory disease despite treatment with standard disease modifying therapy (DMT) including at least 6 months of interferon or Copaxone. Inflammatory disease is defined based on either MRI (gadolinium enhancing lesion, new T2 lesion) or *steroid-treated clinical relapses (prescribed by a neurologist)
•Minimum disease activity required:
•Failed a first line DMT (Copaxone or Interferon), defined as two or more *steroid treated clinical relapses within the last 12 months. A clinical relapse may also be evidence of active inflammation on MRI (gadolinium enhancing lesion or new T2 lesion) in the last 12 months on two MRIs at least three months apart
•Failed a second or third line MS Drug: Zinbryta (daclizumab), Aubagio (teriflunomide), Gilenya (fingolimod), Tecifidera (dimethyl fumarate), Lemtrada (alemtuzumab), Ocrevus (ocrelizumab), Tysabri (natalizumab), Rituxan (rituximab) or IVIg, defined as one *steroid treated clinical relapse within the last 12 months or evidence of active inflammation on MRI (gadolinium enhancing lesion or new T2 lesion) in the last 12 months.
•Cognitive dysfunction that prevents gainful employment, but competent to comply with treatment and informed consent
•A steroid-treated relapse will include a relapse that was severe enough to justify treatment but due to patient intolerance of steroids, they were offered but not used.

排除标准

•Any adult who is unable to consent (for adults who are cognitively impaired due to MS, consent may be obtained from the closest living relative or person who has power of attorney)
•Individuals under the age of 18 or over the age of 58
•Diagnosis of Primary Progressive MS, Secondary Progressive MS, or Clinically Isolated Syndrome (CIS)
•Pregnant women (positive serum or urine human chorionic gonadotropin (HCG) test)
•Women who are breastfeeding
•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
•Any prior chemotherapy or radiation therapy (except for cyclophosphamide used to treat MS disease)
•History of sickle cell disease (SS), SC disease, coagulopathy, or if actively receiving anticoagulation therapy
•History of insulin-dependent diabetes
•Inability or unwillingness to pursue effective means of birth control from the time of evaluation for eligibility until 6 months post-transplant. 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) with every act of intercourse, use of diaphragm with contraceptive jelly and/or use of condom 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)
•Diffusing capacity of the lungs for carbon monoxide (DLCO) < 60% of predicted
•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
•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 Tysabri (natalizumab) within the previous six months
•Use of Gilenya (fingolimod) within the previous three months
•Use of Tecfidera (dimethyl fumarate) within the previous three months
•Use of Aubagio (teriflunomide) 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
•Use of Lemtrada/Campath (alemtuzumab) within previous 12 months
•Use of Rituxan (rituximab) or Ocrevus (ocrelizumab) within previous four months
•Prior treatment with Novantrone (mitoxantrone)
•Any hereditary neurological disease such as Charcot-Marie-Tooth disease (CMT), Spinocerebellar ataxia (SCA), or Parkinson's Disease
•Severe or symptomatic cervical spinal stenosis unless surgically corrected
•Myocardial infarction within last 12 months; if longer than 12 months, must pass dobutamine stress test and be cleared by cardiology

研究组 & 干预措施

Control Arm

Experimental

Hematopoietic Stem Cell Therapy will be performed as follows: Autologous stem cells will be infused after conditioning with cyclophosphamide, mesna, rATG (rabbit), and methylprednisolone. Granulocyte-colony stimulating factor (G-CSF) will be administered post-transplant.

干预措施: Cyclophosphamide (Drug)

Control Arm

Experimental

干预措施: Mesna (Drug)

Control Arm

Experimental

干预措施: rATG (Drug)

Control Arm

Experimental

干预措施: Methylprednisolone (Drug)

Control Arm

Experimental

干预措施: G-CSF (Drug)

Control Arm

Experimental

干预措施: Autologous Stem Cells (Biological)