Addition of Belimumab to B-cell Depletion in Relapsing-remitting Multiple Sclerosis
Condition: Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis
Intervention: Belimumab; Short-course Ocrelizumab; Continued Ocrelizumab
Intervention description: 200 mg SC weekly for 36 months; 300 mg, two infusions two weeks apart and then 600 mg as a single infusion after six months (only one time) (total of two courses of treatment); 300 mg, two infusions two weeks apart and then 600 mg as a single infusion every six months for a total of 36 months
Intervention MeSH terms: Belimumab; Ocrelizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 4.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      Multiple sclerosis is the most common inflammatory disease of the central nervous system and
      a common cause of disability in young adults. Depleting B cells from the circulation with an
      anti-cluster of differentiation (CD) 20 antibodies has proven to be an effective strategy in
      reducing relapses and disability in patients with the relapsing-remitting disease. However,
      continuous and long-term depletion of B-cells can result in reduced immunoglobulin levels,
      immunosuppression, and an increased tendency for severe infections and perhaps, even
      malignancy.

      Blocking B-cell Activating Factor (BAFF) is effective for the treatment of several autoimmune
      disorders. Belimumab, a BAFF blocking antibody, has been approved by the Food and Drug
      Administration for the treatment of systemic lupus erythematosus. Belimumab has been shown to
      have immunomodulatory properties, without resulting in overt immunosuppression.

      The investigators hypothesize that belimumab, given to patients who received a short course
      of treatment with B-cell depleting antibody (ocrelizumab), will be safe and equally effective
      in reducing MS disease activity (as compared to patients receiving continuous treatment with
      ocrelizumab); while resulting in less immunosuppression, as measured by antibody response to
      pneumococcal vaccination. Currently, available treatment strategies in relapsing MS sacrifice
      higher efficacy for long-term safety or vice versa. The proposed strategy in this application
      combines the long-term safety and high efficacy to treat patients with relapsing-remitting
      multiple sclerosis (RRMS) and, if eventually proven effective, can be adopted in a large
      proportion of patients with this chronic disease.

      This is a randomized, open-labeled trial. Forty eligible participants will be randomized 1:1
      to either receiving a form of standard of care, ocrelizumab (300 mg two infusions two weeks
      apart at baseline and then 600 mg as a single infusion every six months) or belimumab (200 mg
      subcutaneous (SC) weekly for 36 months) plus two courses of ocrelizumab (300 mg two infusions
      two weeks apart at baseline and 600 mg as a single infusion six months later). Co-primary
      outcomes of the study include pneumococcal vaccine antibody response, the return of MS
      disease activity, and proportions of patients with adverse events and serious adverse events.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Diagnosis of RRMS based on McDonald criteria 2017

          -  Age > 18

          -  A clinical relapse in the past 12 months OR an enhancing lesion on brain/ spinal cord
             MRI in the past 6 months OR a new T2/FLAIR lesion on a brain/spinal cord MRI obtained
             in the past 6 months (compared to a previous MRI obtained within one year from the
             latest MRI)

          -  Pre-existing pneumococcal antibody titers (>1.0 mg/mL) to =<9 of 23 vaccine serotypes

          -  Female Subjects: Not pregnant or nursing and at least one of the following conditions
             apply: a. Non- childbearing potential defined as pre-menopausal females with a
             documented tubal ligation or hysterectomy or postmenopausal defined as 12 months of
             spontaneous amenorrhea. b. Child-bearing potential and agrees to use one of the
             contraception methods as described by the investigator or designee, from Day 0 until
             24 weeks after the last dose of study medications (See details below).

          -  Liver function at the time of screening: alanine aminotransferase (ALT) < 2x upper
             limit of normal (ULN); bilirubin <= 1.5x ULN (isolated bilirubin >1.5x ULN is
             acceptable if bilirubin is fractionated and direct bilirubin <35%).

        Exclusion Criteria:

          -  Prior therapy at any time: has ever received any of the following: a) B-cell targeted
             therapy (e.g., rituximab, ocrelizumab, other anti-cluster of differentiation (CD)20
             agents, anti-CD22 [epratuzumab], anti-CD52 [alemtuzumab], B lymphocyte stimulator
             (BLyS)-receptor fusion protein [BR3], Transmembrane activator and calcium-modulating
             ligand (CAML) interaction (TACI) fragment, crystallizable (Fc), or belimumab)

          -  Prior use of cladribine, mitoxantrone, cyclophosphamide, or hematopoietic stem cell
             transplantation (HSCT)

          -  Lymphopenia: a lymphocyte count <500/ millimeter (mm)^3

          -  Neutrophils <1.5x 10E9/L.

          -  Drug sensitivity: a history of sensitivity to any of the study medications, or
             components thereof or a history of drug or other allergies including a previous
             anaphylactic reaction to parenteral administration contrast agents, human or murine
             proteins or monoclonal antibodies

          -  Treatment with steroids in the last 30 days

          -  Clinically unstable medical or psychiatric disorder

          -  Have evidence of serious suicide risk including any history of suicidal behavior in
             the last 6 months and/or any suicidal ideation in the last 2 months or who in the
             investigator's judgment, poses a significant suicide risk

          -  Have a history of an anaphylactic reaction to parenteral administration of contrast
             agents, human or murine proteins or monoclonal antibodies

          -  Substance abuse: has evidence of current drug or alcohol abuse or dependence

          -  365 Day prior therapy: has received a biologic investigational agent other than B-cell
             targeted therapy [e.g., abetimus sodium, anti CD40L antibody (e.g., BG9588/ IDEC-131;
             investigational agent applies to any drug not approved for sale in the country in
             which it is being used]

          -  30 Day prior therapy: has received any of the following within 30 days before Day 0:
             a) Any other MS disease-modifying therapy, not mentioned above (including fumaric acid
             esters, sphingosine-1-phosphate (S1P) receptor modulators, teriflunomide, and
             natalizumab). Glatiramer acetate and interferons are permitted up to the day of
             starting the investigational medication. Intravenous, oral, and Inhaled steroids and
             new topical immunosuppressive agents (e.g., eye drops, topical creams) are allowed.

          -  30 Day prior therapy: has received a live virus vaccine or a non-biologic
             investigational agent.

          -  Malignancy: has a history of malignancy in the past 5 years except for adequately
             treated cancers of the skin (basal or squamous cell) or carcinoma in situ of the
             uterine cervix.

          -  Have a history of a primary immunodeficiency

          -  Have a significant IgG deficiency (IgG level < 400 mg/dL)

          -  Have an IgA deficiency (IgA level < 10 mg/dL)

          -  Infection history:

               -  Currently on any suppressive therapy for chronic infection (such as tuberculosis,
                  pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster, and atypical
                  mycobacteria)

               -  Hospitalization for treatment of infection within 60 days of Day 0.

               -  Use of parenteral (IV or IM) antibiotics (anti-bacterial, antiviral, anti-fungal,
                  or anti-parasitic agents) within 60 days of Day 0

          -  Other disease/conditions: has any of the following: a) clinical evidence of
             significant unstable or uncontrolled acute or chronic diseases (i.e., cardiovascular,
             pulmonary, hematologic, gastrointestinal, hepatic, neurological, malignancy or
             infectious diseases) which, in the opinion of the investigator, could confound the
             results of the study or put the subject at undue risk; b) a surgical procedure planned
             in the 6 months after Day 0; c) a known history of any other medical disease (e.g.,
             cardiopulmonary), laboratory abnormality, or condition (e.g., poor venous access)
             that, in the opinion of the investigator, makes the subject unsuitable for the study

          -  Hepatitis status:

               -  Serologic evidence of current or past Hepatitis B (HB) infection based on the
                  results of testing for HBsAg and HBcAb as follows: Patients positive for HBsAg or
                  HBcAb are excluded

               -  A positive test for Hepatitis C antibody

          -  HIV: known to have a historically positive HIV test or tests positive at screening for
             HIV.

          -  Laboratory abnormalities: has an abnormal laboratory assessment, which is judged
             clinically significant by the investigator.

          -  Drug Sensitivity: has a history of sensitivity to any of the study medications, or
             components thereof or a history of drug or other allergies including a previous
             anaphylactic reaction to parenteral administration contrast agents, human or murine
             proteins or monoclonal antibodies that, in the opinion of the investigator or Medical
             Monitor, contraindicates their participation.

          -  Any contraindication to undergoing MRI