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SUPPRESS: Sequential Natalizumab - Alemtuzumab Therapy in Patients With Relapsing Forms of Multiple Sclerosis

Sponsor
University of Texas Southwestern Medical Center (Other)
Overall Status
Completed
CT.gov ID
NCT03135249
Collaborator
Genzyme, a Sanofi Company (Industry)
9
Enrollment
2
Locations
1
Arm
30.2
Actual Duration (Months)
4.5
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if a sequential combination therapy of natalizumab and alemtuzumab induces peripheral tolerance and reduces the annualized relapse rate (ARR) in patients with relapsing-remitting multiple sclerosis (RRMS).

Condition or Disease Intervention/Treatment Phase
Phase 4

Detailed Description

To determine if treatment with alemtuzumab after natalizumab reduces the ARR in patients with RRMS. The goal of this trial is to establish a disease-free state over a 24 months period in patients who received the natalizumab-alemtuzumab sequential therapy. The target population for this study are RRMS patients nearing the end of their natalizumab treatment regimen.Participants will be recruited from four different sites. Patients who meet all inclusion/exclusion criteria will be eligible for enrollment in the study.

Alemtuzumab (Lemtrada®) will be administered at a dose of 12 mg/d by intravenous (i.v.) infusion every day for five consecutive days within 14 days of the last dose of natalizumab. After 12 months, patients will be treated with a second course of alemtuzumab 12 mg/d by intravenous (i.v.) infusion every day for three consecutive days, and participants will be followed open-label for another 12 months per standard of care. Outside the scope of this study, the intention is to follow all study participants in participating centers long-term, and to record disease activity and treatment response.

Natalizumab treatment sequesters leukocytes out of the central nervous system (CNS) into the peripheral blood. Immediate sequential alemtuzumab therapy will deplete these cells more completely than alemtuzumab monotherapy, and prevent reactivation of disease activity previously treated with natalizumab. Thus, investigators hypothesize that sequential natalizumab - alemtuzumab therapy will prevent disease activation after cessation of natalizumab, and will provide sustained disease remission in many patients.

Clinical follow up by the treating physician will occur at months 0, 3, 6, 9, 12, 18 and 24 or immediately following clinical exacerbations months. During clinical visits, comprehensive medical history data will be obtained by the treating physician. Clinical visits due to suspected exacerbations associated with CNS (central nervous system) demyelination, and associated diagnostic studies and treatments, will be covered under the medical standard of care by third party payers. A recommendation to reevaluate the patient within 3 months following the clinical event to assess for extent of recovery will be made.

Standardized MRI studies of the brain will be performed at 0, 6, 12 and 24 months. Clinical imaging studies of the brain will be performed during or immediately following the onset of a clinical exacerbation will be performed at the discretion of the site PI with scan costs covered under the medical standard of care. An end of study clinical MRI of the brain with and without contrast will be recommended to study participants at week 96 as medical standard of care.

Study Design

Study Type:
Interventional
Actual Enrollment :
9 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Intervention Model Description:
To determine if treatment with alemtuzumab after natalizumab maintains or reduces the ARR in patients with RRMS. The goal of this trial is to establish a disease-free state over a 24 months period in patients who received the natalizumab-alemtuzumab sequential therapy.To determine if treatment with alemtuzumab after natalizumab maintains or reduces the ARR in patients with RRMS. The goal of this trial is to establish a disease-free state over a 24 months period in patients who received the natalizumab-alemtuzumab sequential therapy.
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Sequential Natalizumab - Alemtuzumab Therapy in Patients With Relapsing Forms of Multiple Sclerosis (SUPPRESS)
Actual Study Start Date :
May 1, 2018
Actual Primary Completion Date :
Nov 4, 2020
Actual Study Completion Date :
Nov 4, 2020

Arms and Interventions

Arm Intervention/Treatment
Other: Alemtuzumab treatment.

Patients with relapsing-remitting multiple sclerosis previously treated with natalizumab, the following treatment arms with alemtuzumab will be implemented: Year One: Alemtuzumab 12 mg (1.2 ml) IV Infusion via pump over a minimum of four hours daily for five days to be given within eight hours after dilution. Year Two: Alemtuzumab 12 mg (1.2 ml) IV Infusion via pump over a minimum of four hours daily for three days to be given within eight hours after dilution.

Drug: Alemtuzumab
Alemtuzumab is a humanized monoclonal therapeutic antibody that rapidly depletes cluster of differentiation 52 (CD52)+ cells.
Other Names:
  • Lemtrada

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Annualized Relapse Rate (ARR) From the Time of Cessation of Natalizumab Treatment. [12 months]

      The goal of this trial is to establish a disease-free state over a 24 months period in patients who received the natalizumab-alemtuzumab sequential therapy. ARR was the number of confirmed relapses in a year, calculated as the total number of relapses for all participants in the treatment group divided by the total participant-years of time in study.

    2. Relapse-free Period [Baseline until progression up to 12 months]

      Relapse free period, number of months until relapse, was measured only among participants who may relapse.

    Secondary Outcome Measures

    1. Number of New T2 Lesions [12 months]

      Number of new T2 lesions as measured by MRI.

    2. Number of Enlarging T2 Lesions [12 months]

      Number of enlarging T2 lesions as measured by MRI.

    3. Number of Gadolinium (Gd)-Enhancing Lesions [12 months]

      Number of gadolinium (Gd)-enhancing lesions as measured by MRI.

    Other Outcome Measures

    1. Neurological Disability Outcome [12 months]

      Neurological disability The Expanded Disability Status Scale (EDSS) will be utilized to measure the accumulation of neurological disability. The EDSS is a scale providing a disability score (0 to 10) based on neurological examination and information about how the patient is able to perform tasks such as long walking. Higher the score, worse the outcomes.

    2. Quality of Life Outcome [12 months]

      Quality of life (QoL) will be measured by a pre-defined, self-administered testing battery. It measures the pleasure one derives from being able to do their work well, feelings of hopelessness and difficulties in dealing with work or in doing their job effectively, and work-related, secondary exposure to extremely stressful events. Possible scores range from 0-100, with higher scores indicating a better quality of life.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 60 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    1. Age between 18 and 60 years, inclusive.

    2. Diagnosis of relapsing forms of MS using revised McDonald Criteria1.

    3. Expanded Disability Status Scale (EDSS) 0 - 5.5 (note: functional system changes in cerebral (or mental) functions and in bowel and bladder functions not used in determining EDSS for protocol eligibility).

    4. Has had a minimum of 12 monthly doses of continuous natalizumab therapy (300 mg/d).

    5. Understands English, and gives informed consent.

    Exclusion Criteria:

    1. Natalizumab failure based on clinician's discretion.

    2. Any prior exposure to alemtuzumab.

    3. Progressive MS.

    4. A diagnosis of Progressive multifocal leukoencephalopathy (PML).

    5. Known hypersensitivity to alemtuzumab.

    6. Initiation of new immunosuppressant treatment after the subject becomes protocol-eligible (except for corticosteroids) or enrollment in a concurrent trial with immuno-active pharmacotherapies.

    7. Uncontrolled diabetes mellitus defined as HbA1c > 8% and/or requiring intensive management.

    8. History of cytopenia consistent with the diagnosis of myelodysplastic syndrome.

    9. Clinically significant autoimmune disease other than MS that may affect the CNS, including neuromyelitis optica (NMO), systemic lupus erythematosus (SLE), or Behcet disease.

    10. Active hepatitis B or C infection or evidence of cirrhosis.

    11. HIV positivity.

    12. Uncontrolled viral, fungal, or bacterial infection.

    13. Positive pregnancy test or inability or unwillingness to use effective means of birth control. Effective birth control is defined as:

    14. Refraining from all acts of vaginal intercourse (abstinence),

    15. Consistent use of birth control pills,

    16. Tubal sterilization or male partner who has undergone vasectomy

    17. Placement of intrauterine device

    18. Use, with every act of intercourse, of a diaphragm with contraceptive jelly and/or condoms with contraceptive foam.

    19. Presence of metallic objects implanted in the body that would preclude the ability of the subject to safely have MRI exams.

    20. Psychiatric illness, mental deficiency, or cognitive dysfunction making compliance with treatment or informed consent impossible.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 VA North Texas Health Care System Dallas Texas United States 75216
    2 UT Southwestern Medical center Dallas Texas United States 75390

    Sponsors and Collaborators

    • University of Texas Southwestern Medical Center
    • Genzyme, a Sanofi Company

    Investigators

    • Principal Investigator: Olaf Stuve, M.D., Ph.D., UT Southwestern Medical Center

    Study Documents (Full-Text)

    More Information

    Publications

    Responsible Party:
    Olaf Stuve, PROFESSOR, University of Texas Southwestern Medical Center
    ClinicalTrials.gov Identifier:
    NCT03135249
    Other Study ID Numbers:
    • STU 112016-060
    First Posted:
    May 1, 2017
    Last Update Posted:
    Feb 15, 2022
    Last Verified:
    Jan 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Undecided
    Plan to Share IPD:
    Undecided
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    Yes
    Additional relevant MeSH terms:
    Multiple Sclerosis
    Sclerosis
    Alemtuzumab

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Alemtuzumab Treatment.
    Arm/Group Description Patients with relapsing-remitting multiple sclerosis previously treated with natalizumab, the following treatment arms with alemtuzumab will be implemented: Year One: Alemtuzumab 12 mg (1.2 ml) IV Infusion via pump over a minimum of four hours daily for five days to be given within eight hours after dilution. Year Two: Alemtuzumab 12 mg (1.2 ml) IV Infusion via pump over a minimum of four hours daily for three days to be given within eight hours after dilution. Alemtuzumab: Alemtuzumab is a humanized monoclonal therapeutic antibody that rapidly depletes cluster of differentiation 52 (CD52)+ cells.
    Period Title: Overall Study
    STARTED 9
    COMPLETED 7
    NOT COMPLETED 2

    Baseline Characteristics

    Arm/Group Title Alemtuzumab Treatment.
    Arm/Group Description Patients with relapsing-remitting multiple sclerosis previously treated with natalizumab, the following treatment arms with alemtuzumab will be implemented: Year One: Alemtuzumab 12 mg (1.2 ml) IV Infusion via pump over a minimum of four hours daily for five days to be given within eight hours after dilution. Year Two: Alemtuzumab 12 mg (1.2 ml) IV Infusion via pump over a minimum of four hours daily for three days to be given within eight hours after dilution. Alemtuzumab: Alemtuzumab is a humanized monoclonal therapeutic antibody that rapidly depletes cluster of differentiation 52 (CD52)+ cells.
    Overall Participants 9
    Age (Count of Participants)
    <=18 years
    0
    0%
    Between 18 and 65 years
    9
    100%
    >=65 years
    0
    0%
    Sex: Female, Male (Count of Participants)
    Female
    7
    77.8%
    Male
    2
    22.2%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    2
    22.2%
    White
    7
    77.8%
    More than one race
    0
    0%
    Unknown or Not Reported
    0
    0%
    Region of Enrollment (Count of Participants)
    United States
    9
    100%

    Outcome Measures

    1. Primary Outcome
    Title Annualized Relapse Rate (ARR) From the Time of Cessation of Natalizumab Treatment.
    Description The goal of this trial is to establish a disease-free state over a 24 months period in patients who received the natalizumab-alemtuzumab sequential therapy. ARR was the number of confirmed relapses in a year, calculated as the total number of relapses for all participants in the treatment group divided by the total participant-years of time in study.
    Time Frame 12 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Alemtuzumab Treatment.
    Arm/Group Description Patients with relapsing-remitting multiple sclerosis previously treated with natalizumab, the following treatment arms with alemtuzumab will be implemented: Year One: Alemtuzumab 12 mg (1.2 ml) IV Infusion via pump over a minimum of four hours daily for five days to be given within eight hours after dilution. Year Two: Alemtuzumab 12 mg (1.2 ml) IV Infusion via pump over a minimum of four hours daily for three days to be given within eight hours after dilution. Alemtuzumab: Alemtuzumab is a humanized monoclonal therapeutic antibody that rapidly depletes cluster of differentiation 52 (CD52)+ cells.
    Measure Participants 9
    Mean (95% Confidence Interval) [number of relapses in a year]
    0
    2. Primary Outcome
    Title Relapse-free Period
    Description Relapse free period, number of months until relapse, was measured only among participants who may relapse.
    Time Frame Baseline until progression up to 12 months

    Outcome Measure Data

    Analysis Population Description
    We are intending to report the number of months until relapse and no relapses occurred. This outcome was not measured because there was no relapse.
    Arm/Group Title Alemtuzumab Treatment.
    Arm/Group Description Patients with relapsing-remitting multiple sclerosis previously treated with natalizumab, the following treatment arms with alemtuzumab will be implemented: Year One: Alemtuzumab 12 mg (1.2 ml) IV Infusion via pump over a minimum of four hours daily for five days to be given within eight hours after dilution. Year Two: Alemtuzumab 12 mg (1.2 ml) IV Infusion via pump over a minimum of four hours daily for three days to be given within eight hours after dilution. Alemtuzumab: Alemtuzumab is a humanized monoclonal therapeutic antibody that rapidly depletes cluster of differentiation 52 (CD52)+ cells.
    Measure Participants 0
    3. Secondary Outcome
    Title Number of New T2 Lesions
    Description Number of new T2 lesions as measured by MRI.
    Time Frame 12 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Alemtuzumab Treatment.
    Arm/Group Description Patients with relapsing-remitting multiple sclerosis previously treated with natalizumab, the following treatment arms with alemtuzumab will be implemented: Year One: Alemtuzumab 12 mg (1.2 ml) IV Infusion via pump over a minimum of four hours daily for five days to be given within eight hours after dilution. Year Two: Alemtuzumab 12 mg (1.2 ml) IV Infusion via pump over a minimum of four hours daily for three days to be given within eight hours after dilution. Alemtuzumab: Alemtuzumab is a humanized monoclonal therapeutic antibody that rapidly depletes cluster of differentiation 52 (CD52)+ cells.
    Measure Participants 9
    Mean (Standard Deviation) [lesions]
    0
    (0)
    4. Secondary Outcome
    Title Number of Enlarging T2 Lesions
    Description Number of enlarging T2 lesions as measured by MRI.
    Time Frame 12 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Alemtuzumab Treatment.
    Arm/Group Description Patients with relapsing-remitting multiple sclerosis previously treated with natalizumab, the following treatment arms with alemtuzumab will be implemented: Year One: Alemtuzumab 12 mg (1.2 ml) IV Infusion via pump over a minimum of four hours daily for five days to be given within eight hours after dilution. Year Two: Alemtuzumab 12 mg (1.2 ml) IV Infusion via pump over a minimum of four hours daily for three days to be given within eight hours after dilution. Alemtuzumab: Alemtuzumab is a humanized monoclonal therapeutic antibody that rapidly depletes cluster of differentiation 52 (CD52)+ cells.
    Measure Participants 9
    Mean (Standard Deviation) [lesions]
    0
    (0)
    5. Secondary Outcome
    Title Number of Gadolinium (Gd)-Enhancing Lesions
    Description Number of gadolinium (Gd)-enhancing lesions as measured by MRI.
    Time Frame 12 months

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Alemtuzumab Treatment.
    Arm/Group Description Patients with relapsing-remitting multiple sclerosis previously treated with natalizumab, the following treatment arms with alemtuzumab will be implemented: Year One: Alemtuzumab 12 mg (1.2 ml) IV Infusion via pump over a minimum of four hours daily for five days to be given within eight hours after dilution. Year Two: Alemtuzumab 12 mg (1.2 ml) IV Infusion via pump over a minimum of four hours daily for three days to be given within eight hours after dilution. Alemtuzumab: Alemtuzumab is a humanized monoclonal therapeutic antibody that rapidly depletes cluster of differentiation 52 (CD52)+ cells.
    Measure Participants 9
    Mean (Standard Deviation) [lesions]
    0
    (0)
    6. Other Pre-specified Outcome
    Title Neurological Disability Outcome
    Description Neurological disability The Expanded Disability Status Scale (EDSS) will be utilized to measure the accumulation of neurological disability. The EDSS is a scale providing a disability score (0 to 10) based on neurological examination and information about how the patient is able to perform tasks such as long walking. Higher the score, worse the outcomes.
    Time Frame 12 months

    Outcome Measure Data

    Analysis Population Description
    2 patients did not complete a 12 month EDSS assessment.
    Arm/Group Title Alemtuzumab Treatment.
    Arm/Group Description Patients with relapsing-remitting multiple sclerosis previously treated with natalizumab, the following treatment arms with alemtuzumab will be implemented: Year One: Alemtuzumab 12 mg (1.2 ml) IV Infusion via pump over a minimum of four hours daily for five days to be given within eight hours after dilution. Year Two: Alemtuzumab 12 mg (1.2 ml) IV Infusion via pump over a minimum of four hours daily for three days to be given within eight hours after dilution. Alemtuzumab: Alemtuzumab is a humanized monoclonal therapeutic antibody that rapidly depletes cluster of differentiation 52 (CD52)+ cells.
    Measure Participants 7
    Mean (Standard Deviation) [score on a scale]
    3.14
    (1.49)
    7. Other Pre-specified Outcome
    Title Quality of Life Outcome
    Description Quality of life (QoL) will be measured by a pre-defined, self-administered testing battery. It measures the pleasure one derives from being able to do their work well, feelings of hopelessness and difficulties in dealing with work or in doing their job effectively, and work-related, secondary exposure to extremely stressful events. Possible scores range from 0-100, with higher scores indicating a better quality of life.
    Time Frame 12 months

    Outcome Measure Data

    Analysis Population Description
    We were not able to collect data for 2 out of 6 participants at UTSW and 3 participants at subsite were administered incorrect versions of the questionnaire which cannot be compared to the version they were supposed to and hence not analyzed for these participants.
    Arm/Group Title Alemtuzumab Treatment.
    Arm/Group Description Patients with relapsing-remitting multiple sclerosis previously treated with natalizumab, the following treatment arms with alemtuzumab will be implemented: Year One: Alemtuzumab 12 mg (1.2 ml) IV Infusion via pump over a minimum of four hours daily for five days to be given within eight hours after dilution. Year Two: Alemtuzumab 12 mg (1.2 ml) IV Infusion via pump over a minimum of four hours daily for three days to be given within eight hours after dilution. Alemtuzumab: Alemtuzumab is a humanized monoclonal therapeutic antibody that rapidly depletes cluster of differentiation 52 (CD52)+ cells.
    Measure Participants 4
    Mean (Standard Deviation) [score on a scale]
    71.38
    (21.04)

    Adverse Events

    Time Frame Up to 12 months
    Adverse Event Reporting Description
    Arm/Group Title Alemtuzumab Treatment.
    Arm/Group Description Patients with relapsing-remitting multiple sclerosis previously treated with natalizumab, the following treatment arms with alemtuzumab will be implemented: Year One: Alemtuzumab 12 mg (1.2 ml) IV Infusion via pump over a minimum of four hours daily for five days to be given within eight hours after dilution. Year Two: Alemtuzumab 12 mg (1.2 ml) IV Infusion via pump over a minimum of four hours daily for three days to be given within eight hours after dilution. Alemtuzumab: Alemtuzumab is a humanized monoclonal therapeutic antibody that rapidly depletes cluster of differentiation 52 (CD52)+ cells.
    All Cause Mortality
    Alemtuzumab Treatment.
    Affected / at Risk (%) # Events
    Total 0/9 (0%)
    Serious Adverse Events
    Alemtuzumab Treatment.
    Affected / at Risk (%) # Events
    Total 0/9 (0%)
    Other (Not Including Serious) Adverse Events
    Alemtuzumab Treatment.
    Affected / at Risk (%) # Events
    Total 0/9 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Dr. Olaf Stuve, Principal Investigator
    Organization UT Southwestern Medical Center
    Phone 12146484559
    Email olaf.stuve@utsouthwestern.edu
    Responsible Party:
    Olaf Stuve, PROFESSOR, University of Texas Southwestern Medical Center
    ClinicalTrials.gov Identifier:
    NCT03135249
    Other Study ID Numbers:
    • STU 112016-060
    First Posted:
    May 1, 2017
    Last Update Posted:
    Feb 15, 2022
    Last Verified:
    Jan 1, 2022