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Optimal Conditioning Regimen for Autologous Transplantation of Relapsing Remitting Multiple Sclerosis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05482542
Recruitment Status : Recruiting
First Posted : August 1, 2022
Last Update Posted : August 17, 2022
Sponsor:
Information provided by (Responsible Party):
Scripps Health

Brief Summary:
This study is designed to compare two non-myeloablative conditioning regimens (combination of chemotherapy and immune specific proteins against immune cells) for relapsing remitting multiple sclerosis (RRMS). The two conditioning regimens are the most commonly used world wide in clinical practice for the treatment of multiple sclerosis (MS). The first investigational conditioning regimen is cyclophosphamide (chemotherapy) and rATG (rabbit anti-thymocyte globulin, a protein against immune cells). The second investigational conditioning regimen includes the same dose of cyclophosphamide (chemotherapy) and rituximab (a protein against immune cells). Both cyclophosphamide and either rATG or rituximab are given to kill immune cells that are thought to be causing MS, followed by return of one's own previously collected blood stem cells (autologous stem cell transplant) to hasten recovery. The goal of this study is to assess the difference of these treatments in terms of toxicity and efficacy.

Condition or disease Intervention/treatment Phase
Multiple Sclerosis, Relapsing-Remitting Other: Autologous hematopoietic stem cell transplantation Drug: Cyclophosphamide/ATG Drug: Cyclophosphamide/Rituximab Not Applicable

Detailed Description:
Autologous hematopoietic stem cell transplantation (HSCT) in patients with active relapsing remitting multiple sclerosis (RRMS) halts disease progression, improves neurologic disability and quality of life, and provides a prolonged drug-free remission. A "position paper" by neurologists and hematologists under the American Society of Transplant and Cellular Therapy (ASTCT) has recommended autologous HSCT as standard of care, clinical evidence available, for treatment-refractory relapsing MS with high risk of future disability. Similarly, the EBMT has recommended the use of HSCT as "standard or care" for patients with highly active RRMS failing at least one DMT. Currently, the optimal conditioning regimen in terms of safety and efficacy is unknown. Herein, we will compare the two most commonly used regimens cyclophosphamide/ATG, or cyclophosphamide/rituximab in terms of safety and efficacy.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Optimal Conditioning Regimen Protocol for Autologous Hematopoietic Stem Cell Transplantation of Relapsing Remitting Multiple Sclerosis
Estimated Study Start Date : September 1, 2022
Estimated Primary Completion Date : July 1, 2027
Estimated Study Completion Date : July 1, 2027

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Cyclophosphamide/ATG Conditioning Regimen
Cyclophosphamide (200 mg /kg) / rabbit antithymocyte globulin (6.0 mg/kg)
Other: Autologous hematopoietic stem cell transplantation
Autologous hematopoietic stem cell transplantation

Drug: Cyclophosphamide/ATG
Cyclophosphamide/ATG

Cyclophosphamide/Rituximab Conditioning Regimen
Cyclophosphamide (200 mg/kg) / rituximab (1000 mg).
Other: Autologous hematopoietic stem cell transplantation
Autologous hematopoietic stem cell transplantation

Drug: Cyclophosphamide/Rituximab
Cyclophosphamide/Rituximab




Primary Outcome Measures :
  1. Durability of remission between two arms [ Time Frame: Time to first confirmed acute relapse or 5 years after treatment which ever comes first ]
    Defined as the time to first confirmed acute relapse or 5 years after treatment which ever comes first


Secondary Outcome Measures :
  1. Neurologic Disability [ Time Frame: From initiation of study to completion, up until 5 years after treatment ]
    Defined by change in EDSS (Expanded Disability Status Scale, ranges from 0 to 10 with 0 normal and 10 worst)

  2. Quality of Life [ Time Frame: From initiation of study to completion, up until 5 years after treatment ]
    Defined by the SF-36 questionnaire (scale of 0 to 100, lower score corresponds with more disability)

  3. Safety [ Time Frame: From initiation of study to completion, up until 5 years after treatment ]
    Defined by mortality (treatment related and all causes), during HSCT at first 100 days, one year, and last evaluation up to 5 years



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 58 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age 18-58 years old
  2. MRI T2 hyperintense lesions with at least 1 lesion in two or more of the following locations: periventricular, cortical or juxtacortical, infratentorial, or 1 spinal lesion
  3. Since diagnosis a new MRI T2 lesion or since diagnosis a gadolinium positive lesion and at least one T2 weighted lesion
  4. RRMS with a history of:

    1. 2 or more "active flares" in the prior 12 months despite either copaxone or interferon; or
    2. 1 or more "active flares" in the prior year despite a 2nd or 3rd generation DMT; or
    3. Active secondary progressive MS (aSPMS) with 2 or more gadolinium enhancing lesions with at least 1 gadolinium enhancing lesion > 5 mm in longest dimension within the last 9 months

Exclusion Criteria:

  1. CIS- clinically isolated lesion
  2. isolated optic neuritis
  3. Primary progressive MS b) Nonactive SPSM (defined as no new or enhancing lesions in last 12 months)
  4. spasticity or clinical stiffness of leg(s) unless there is documented new MRI enhancement within the past 12 months.
  5. hyperreflexia or clonus
  6. other immune neurologic disease such as NMO, CIDP, Stiff person syndrome, myasthenia gravis
  7. genetic neurologic diseases such as CMT or spinal cerebellar degeneration
  8. another autoimmune diagnosis such as systemic lupus erythematosus, systemic sclerosis, Behcets, or crohn's disease, etc (with the exception of hypo or hyperthyroidism or history of ITP or AIHA that is in remission)
  9. insulin dependent diabetes mellitus
  10. sickle cell disease
  11. thalassemia major
  12. porphyria
  13. a current or prior cancer / malignancy except for cutaneous basal cell carcinoma or carcinoma in situ (completely excised)
  14. Hepatic:

    1. Liver function test (AST or ALT) > 2 x upper limit of normal or
    2. bilirubin > 2.0 mg /dl
  15. Pulmonary:

    1. DLCO < 60% of normal or;
    2. Asthma not easily corrected with bronchodilator therapy or;
    3. Pulmonary artery hypertension (pulmonary artery systolic pressure (PASP) > 40 mmHg on echocardiogram or by cardiac catheterization a mean pulmonary artery pressure (mPAP) > 25 mmHg; a cardiac catheterization for pulmonary artery pressures is only performed if clinically indicated)
  16. Renal:

    1. creatinine > 2.0 mg/dl, or
    2. nephrotic syndrome
  17. Cardiac:

    1. Acute myocardial infarction (AMI) within the last year, and if history of AMI not being approved by cardiology as low risk or not at increased risk for another AMI: or
    2. Persistent arrythmia not controlled with medication;
    3. Any patient requiring medication for an arrhythmia must be pre-approved by cardiology, or
    4. left ventricular ejection fraction < 45%
  18. Hematology

    1. Hereditary coagulopathy or currently receiving anticoagulation therapy
    2. platelets < 100,000
    3. myelodysplastic syndrome
  19. Infection:

    1. HIV,
    2. hepatitis B
    3. hepatitis C
    4. positive quantiferon gold (tuberculosis test) (may start HSCt once seen by ID and started on anti-tuberculous therapy, that will be continued throughout transplant, if asymptomatic),

    d) active infection at time of hospital admission (except UTI)

  20. EDSS < 2.0 at time of enrollment or insurance submission
  21. Inability to comprehend or give or sign informed consent
  22. Pregnancy (positive serum or urine HCG test) or breast feeding
  23. Failure to comprehend infertility as a complication.
  24. Failure to offer sperm or oocyte collection and storage
  25. Before HSCT failure to be Free of alemtuzumab for 12 months
  26. Before HSCT failure to be Free of natalizumab for 5 months
  27. Before HSCT failure to be Free of rituximab or ocrelizumab for 5 months
  28. Before HSCT failure to be Free of fingolimod for 3 months
  29. Before HSCT failure to be Free of dimethyl fumarate (tecfidera) for 3 months
  30. Before HSCT failure of teriflunomide to have plasma levels < 0.02 mg/L after either oral cholestyramine or activated charcoal clearance.
  31. Prior mitoxantrone
  32. Prior cladribine

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05482542


Contacts
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Contact: RRMS Coordinator 858-554-9100 BurtRRMSTrial@scrippshealth.org
Contact: David J Hermel, MD 858-554-9100 hermel.david@scrippshealth.org

Locations
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United States, California
Scripps Green Hospital Recruiting
La Jolla, California, United States, 92037
Contact: RRMS Coordinator    858-554-9100    BurtRRMSTrial@scrippshealth.org   
Sponsors and Collaborators
Scripps Health
Investigators
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Principal Investigator: James R Mason, MD Scripps Health
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Responsible Party: Scripps Health
ClinicalTrials.gov Identifier: NCT05482542    
Other Study ID Numbers: IRB-21-7874
First Posted: August 1, 2022    Key Record Dates
Last Update Posted: August 17, 2022
Last Verified: August 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Scripps Health:
Autologous Hematopoietic Stem Cell Transplant
Additional relevant MeSH terms:
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Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Cyclophosphamide
Rituximab
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological