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Prevention of Clinical Multiple Sclerosis in Individuals With Radiologically Isolated Disease.

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ClinicalTrials.gov Identifier: NCT04877457
Recruitment Status : Not yet recruiting
First Posted : May 7, 2021
Last Update Posted : May 7, 2021
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Erin Longbrake, Yale University

Brief Summary:
This is a multicenter, randomized, double-blind, placebo-controlled, Phase 4 study in which eligible patients with RADIOLOGICALLY ISOLATED SYNDROME (RIS) (as defined by meeting 2017 McDonald criteria for DIS) will be randomized 1:1 to receive ocrelizumab treatment or placebo (standard of care).

Condition or disease Intervention/treatment Phase
Radiologically Isolated Syndrome Multiple Sclerosis Drug: Ocrelizumab Other: Placebo Phase 4

Detailed Description:
This study is designed to investigate the treatment effect of ocrelizumab compared with placebo on clinical and radiological outcomes in patients with RIS (i.e., asymptomatic CNS lesions fulfilling the 2017 McDonald criteria for DIS), as well as neuroimaging, serologic, immunologic and other exploratory biomarkers of MS disease biology in order to improve the understanding of B cell biology in early disease pathophysiology, characterize the emergence of CNS autoimmunity, and the mechanism of action of ocrelizumab in this population.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Randomization and blinding will be employed to minimize bias in treatment assignment and to provide the basis for valid statistical inference.
Primary Purpose: Prevention
Official Title: A Phase 4, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy of Ocrelizumab in Patients With Radiologically Isolated Syndrome
Estimated Study Start Date : July 2021
Estimated Primary Completion Date : July 2028
Estimated Study Completion Date : July 2028

Resource links provided by the National Library of Medicine

Drug Information available for: Ocrelizumab

Arm Intervention/treatment
Experimental: Ocrelizumab
Three courses of ocrelizumab will be administered over the course of the study.
Drug: Ocrelizumab
The first course of ocrelizumab will be administered as two 300 mg infusions at Week 0 (Day 1) and Week 2 (Day 15), with the subsequent second- and third-courses given as a single 600 mg infusion at Weeks 24 and 48.

Placebo Comparator: Placebo
Three courses of placebo will be administered over the course of the study.
Other: Placebo
Placebo will be administered at Week 0 (Day 1) and Week 2 (Day 15), with the subsequent second- and third-courses given at Weeks 24 and 48.




Primary Outcome Measures :
  1. Time to development of first new radiologic or clinical evidence of MS [ Time Frame: Up 4 years ]
    The primary efficacy endpoint for this study is to evaluate the efficacy of ocrelizumab compared with placebo on delaying the time to development of new radiological or clinical evidence of MS, defined as the time from baseline to first new T1 gadolinium-enhancing lesions and/or new or enlarging T2 lesions consistent with MS OR first clinical evidence of MS, i.e., neurological event resulting from CNS demyelination as evidenced by acute or progressive clinical syndrome consistent with MS.


Secondary Outcome Measures :
  1. Cumulative number of new or enlarging T2 lesions [ Time Frame: Up to 4 years ]
    MRI scans will be used to determine the number of new or enlarging T2 lesions

  2. Change in T2-lesion volume [ Time Frame: Baseline, 24 weeks, 48 weeks, 72 weeks, 104 weeks, 156 weeks, 208 weeks ]
    MRI scans will be used to the change in T2 lesions

  3. Cumulative number of new T1 gadolinium-enhancing lesions [ Time Frame: Up to 4 years ]
    MRI scans will be used to determine the cumulative number of new T1 gadolinium-enhancing lesions

  4. Change in total brain volume [ Time Frame: Baseline, 24 weeks, 48 weeks, 72 weeks, 104 weeks, 156 weeks, 208 weeks ]
    MRI scan will be used to determine the change in total brain volume

  5. Change in total spinal cord volume [ Time Frame: Baseline, 24 weeks, 48 weeks, 72 weeks, 104 weeks, 156 weeks, 208 weeks ]
    MRI scan will be used to determine the change in total brain volume

  6. Change in serum NfL (sNfL) [ Time Frame: Baseline, 24 weeks, 48 weeks, 72 weeks, 104 weeks, 130 weeks, 156 weeks, 182 weeks, 208 weeks ]
    Change in serum Nfl will be used measured



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Established RIS diagnosis (i.e. CNS lesions consistent with MS, meeting McDonald 2017 criteria for DIS), either diagnosed within the last 5 years or known to have had accumulation of CNS lesions within the last 5 years.
  • No prior exposure to DMT or long-term immunomodulatory medications

Exclusion Criteria:

  • Intolerance to gadolinium-based contrast agent
  • Contraindications to MRI
  • ≥5 years of radiologic stability since first known abnormal MRI for patients previously diagnosed with RIS
  • History of remitting clinical symptoms consistent with MS lasting >24 hours prior to CNS imaging revealing anomalies suggestive of MS
  • CNS MRI anomalies are better accounted for by another disease process
  • Infection Related:
  • Known presence of recurrent or chronic infection (e.g., HIV, syphilis, tuberculosis)
  • History of recurrent aspiration pneumonia requiring antibiotic therapy
  • History or known presence of infectious causes of myelopathy (e.g., syphilis, Lyme disease, HTLV-1, herpes zoster myelopathy)
  • Known active bacterial, viral, fungal, mycobacterial infection, or other infection (including tuberculosis or atypical mycobacterial disease, but excluding fungal infection of nail beds) or any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks prior to baseline visit or oral antibiotics within 2 weeks prior to baseline visit
  • Cancer Related
  • History of cancer, including solid tumors and hematological malignancies (except basal cell, in situ squamous cell carcinomas of the skin, and in situ carcinoma of the cervix or the uterus that have been excised and resolved with documented clean margins on pathology)
  • Pregnant or lactating, or intending to become pregnant during the treatment phase and 6 months after the last infusion of study drug
  • Women of childbearing potential must have a negative serum or urine pregnancy test result within 14 days prior to initiation of study drug
  • Other Medical Conditions
  • History of or currently active primary or secondary immunodeficiency
  • History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies
  • History of alcohol or other drug abuse within 24 weeks prior to enrollment
  • History or known presence of systemic autoimmune disorders associated with systemic symptoms (e.g., lupus, anti-phospholipid antibody syndrome, Sjögren's syndrome, Behçet's disease)
  • Any concomitant disease that may require chronic treatment with systemic corticosteroids or immunosuppressants during the course of the study
  • Significant, uncontrolled disease, as defined by AMA guidelines or similar, such as cardiovascular (including congestive heart failure - NYHA grade 3 or 4, cardiac arrhythmia), uncontrolled hypertension, pulmonary (including chronic obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus), gastrointestinal, or any other significant disease
  • Known presence or history of other neurologic disorders, including but not limited to, the following:

    • Progressive multifocal leukoencephalopathy, CNS or spinal cord tumor, potential metabolic causes of myelopathy (e.g., untreated vitamin B12 deficiency)
    • History of genetically inherited progressive CNS degenerative disorder (e.g., hereditary paraparesis; mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes [MELAS])
    • Neuromyelitis optica spectrum disorders (NMOSD)
    • Ischemic cerebrovascular disorders (e.g., stroke, transient ischemic attack) or ischemia of the spinal cord
    • Severe, clinically significant brain or spinal cord trauma (e.g., cerebral contusion, spinal cord compression)
    • Psychosis not yet controlled by a treatment
  • Drug Related
  • Systemic, high dose corticosteroid therapy within 4 weeks prior to screening
  • Contraindications for, or intolerance to, oral or IV corticosteroids, including IV methylprednisolone, according to the country label, including hypersensitivity to any of the treatment drug constituents
  • Prior exposure to immunomodulatory medications and/or DMT
  • Prior treatment with any disease modifying therapy for MS including but not limited to: interferon (IFN-β-1a (Avonex, Rebif), IFN-β-1b (Betaseron/Betaferon), glatiramer acetate, dimethyl fumarate (DMF; Tecfidera), diroximel fumarate (Vumerity) fingolimod (Gilenya) or siponimod (Mayzent), ozanimod (Zeposia) natalizumab (Tysabri), alemtuzimab (Lemtrada), cladribine (Mavenclad), rituximab (Rituxan), and other anti-CD20 agents
  • Previous treatment with cyclophosphamide, mitoxantrone, azathioprine, mycophenolate mofetil, cyclosporine, methotrexate, total body irradiation, or bone marrow transplantation
  • Previous or concurrent treatment with any investigational agent or treatment with any experimental procedure for MS (e.g., treatment for chronic cerebrospinal venous insufficiency)
  • Vaccinations: Receipt of a live or live-attenuated vaccine or an inactivated/non-live vaccine within 6 weeks prior to enrollment
  • Laboratory: Certain laboratory abnormalities or findings at screening, including the following:
  • Positive serum β-hCG
  • Positive for hepatitis B (hepatitis B surface antigen [HBsAg] positive or hepatitis B core antibody [total HBcAb] confirmed by positive viral DNA polymerase chain reaction [PCR])
  • AST or ALT ≥3.0 ×upper limit of normal
  • Total white blood cell count, including differential counts, below lower limit of normal
  • Absolute lymphocyte count below lower level of normal
  • Absolute neutrophil count below lower limit of normal
  • Platelet count below lower limit of normal

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): NCT04877457


Contacts
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Contact: Julie Holub +1 (203) 737-4784 julie.holub@yale.edu

Sponsors and Collaborators
Yale University
Genentech, Inc.
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Responsible Party: Erin Longbrake, Assistant Professor of Neurology, Yale University
ClinicalTrials.gov Identifier: NCT04877457    
Other Study ID Numbers: 2000029952
ML42790 ( Other Identifier: Genentech, Inc. )
First Posted: May 7, 2021    Key Record Dates
Last Update Posted: May 7, 2021
Last Verified: May 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Multiple Sclerosis
Syndrome
Sclerosis
Disease
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Ocrelizumab
Immunologic Factors
Physiological Effects of Drugs