Ofatumumab Subcutaneous Administration in Subjects With Relapsing-Remitting Multiple Sclerosis
Condition: Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis
Study type: Interventional
Phase: Phase 2

Summary: 
      Ofatumumab is a novel Immunoglobulin 1ĸ ( IgG1ĸ) lytic monoclonal antibody (mAb) that
      specifically binds to the human Cluster of Differentiation 20 (CD20) antigen of which
      expression is restricted to B lymphocytes from the pre-B cell stage to the plasmacytoid
      immunoblast stage only. A recent trial with an anti-CD20 mAb (rituximab) demonstrated that
      targeting B-cells reduces the number of gadolinium-enhancing (GdE) T1 lesions and the relapse
      rate in relapsing-remitting multiple sclerosis (RRMS). Ofatumumab has been shown to be both
      well tolerated and efficacious in several indications, including a small, placebo-controlled
      trial in RRMS using an intravenous (IV) formulation.

      This double-blind, placebo-controlled, parallel-group study will investigate the safety and
      efficacy of a subcutaneous formulation of ofatumumab in the treatment of subjects with RRMS.
      The primary objective of the study is to investigate the efficacy as assessed by magnetic
      resonance imaging. Other objectives will include evaluation of tolerability/safety,
      dose-response relationship, pharmacokinetics, pharmacodynamics, exposure-response, as well as
      other clinical endpoints.
    

Detailed description: 
      Ofatumumab is a novel immunoglobulin G (IgG) 1ĸ lytic monoclonal antibody (mAb) that
      specifically binds to the human CD20 antigen of which expression is restricted to B
      lymphocytes from the pre-B cell stage to the plasmacytoid immunoblast stage only. A recent
      trial with rituximab demonstrated that targeting B-cells reduces the number of
      gadolinium-enhancing (GdE) T1 lesions and the relapse rate in Relapsing-Remitting Multiple
      Sclerosis (RRMS). The intravenous (IV) formulation of ofatumumab has been shown to be both
      well-tolerated and efficacious in Phase I/II & III clinical trials within in B-cell Chronic
      Lymphocytic Leukemia (B-CLL), non-Hodgkin's Follicular Lymphoma (FL), and active Rheumatoid
      Arthritis (RA). A Phase II study of ofatumumab in Relapsing Remitting Multiple Sclerosis
      (RRMS) subjects, OMS115102 (also known as Study GEN414) is ongoing as of the development of
      this protocol. The primary objective of the OMS115102 protocol was to investigate the safety
      of a range of doses (100mg, 300 mg, and 700 mg) of ofatumumab in RRMS subjects, using an IV
      formulation. The treatment period for OMS115102 has been completed; there are currently 4
      subjects ongoing in the Individualized Follow up Phase. In the Week 0 to 24 period the
      majority of subject who were exposed to active treatment with ofatumumab (active/placebo) had
      Cluster of Differentiation 19 (CD19+) and CD20+ levels that were suppressed to zero; recovery
      started for the 100 mg and 300 mg active/placebo groups, at approximately, 12 and 20 weeks
      after discontinuation of dosing with ofatumumab, respectively. In the 700 mg active/placebo
      group, all but one subject had a persistent and complete CD19+ suppression at Week 24. In the
      Week 24 to 48 period, when those who had previously been exposed to placebo were treated with
      ofatumumab (placebo/active), the majority of the subjects treated with ofatumumab had CD19+
      and CD20+ cell levels suppressed to zero (mm3) within one week. Recovery started for the
      subjects in the 100 mg placebo/active group after approximately 16 weeks (from these
      subjects' first infusion). In the 300 mg and 700 mg placebo/active groups, all subjects
      except one (700 mg) had persistent and complete CD19+ suppression at Week 48.

      This study will evaluate the magnetic resonance imaging (MRI) efficacy and will investigate
      the safety of ofatumumab using a subcutaneous (SQ) formulation in subjects with RRMS. This
      Phase II study will be a multi-center, randomized, double-blind, placebo-controlled, dose
      ranging study in subjects with RRMS. Randomization will be stratified based on the absence or
      presence of GdE brain lesions present at screening. The core 54 week period of the study is
      made up of an up to 6-week Screening Phase, a 24-week Treatment Phase, and a 24-week
      Follow-up Phase. Subjects will attend the clinic a total of approximately twelve times
      (including Screening) during this core 54-week period of the study. Subjects who have
      remained enrolled and participate in the study from Screening though the end of the 24-Week
      Follow-Up Period (Week 48 Visit) will be considered completers. Upon completion or withdrawal
      from the core study period, subjects will be followed in the Individualized Follow-up Phase.
      Subjects will return to the clinic every 12 weeks for a B-cell count and other safety
      assessments. Subjects will remain in Individualized Follow-up (IFU) until CD19+ B-lymphocyte
      counts recover to LLN or baseline (if <LLN);OR if B-cell counts have not recovered by the
      Week 120 visit (100 weeks after the last possible treatment dose at Week 20), until either
      the B-cell counts or circulating IgG are >LLN or baseline levels (if <LLN). Male and female
      subjects with a diagnosis of RRMS will be screened for eligibility for the study. All non-MRI
      screening procedures should generally be completed within 14 days of informed consent being
      given. To the extent possible, investigators are to verify subjects meet all non MRI-related
      entry criteria before performing screening MRIs. Subjects who meet all inclusion and
      exclusion criteria will be centrally randomized into the study at the Baseline Visit (Week 0)
      to receive one of the following treatment arms: SQ administration of ofatumumab 3 mg, 30 mg,
      or 60 mg every 12 weeks, 60 mg every 4 weeks, or placebo. Half of the subjects randomized to
      the 30 mg group, or to either of the 60 mg groups, will receive a 3 mg conditioning dose at
      Week 0. Based on tolerability observed in other indications, the 3 mg conditioning dose may
      produce a more gradual lysis of B-cells, thereby reducing the cytokine release reactions to
      the initial 30 mg or 60 mg dose and potentially improve tolerability for subjects. The
      Treatment Phase lasts for 24 weeks and the subject will be seen 8 times during this phase.
      Upon completion or discontinuation of the Treatment Phase, subjects will enter a 24-week
      Follow-up Phase, during which they will not receive investigational product. Ideally, no
      other MS disease-modifying therapies should be taken during this period in order to allow for
      a clean analysis of safety data and the potential for Cluster of Differentiation (CD)+19
      B-lymphocyte cell and immunoglobulin normalization to be assessed. However, if the start of a
      MS disease-modifying therapy is considered medically necessary, follow up will continue
      through the completion of the 24-Week Follow-up Phase. The subject will then be withdrawn
      from the study, and will not enter into the Individualized Follow-up Phase. Upon completion
      of the 24-Week Follow-up Phase, all subjects who have not started an MS disease modifying
      therapy (DMT) will enter the Individualized Follow up. During this Phase, subjects will
      return to the clinic every 12 weeks for a B-cell count and other safety assessments. If a
      subject starts a MS DMT during this follow-up phase they will be withdrawn from the study. To
      the extent possible, subjects experiencing a relapse during the study should return
      immediately to the clinic for evaluation. All MRI scans will be sent to a central reader for
      analysis. An Independent Data Monitoring Committee (IDMC) will evaluate risks relative to
      benefits through review of safety and efficacy information on an ongoing basis during the
      study. Approximately 245 subjects will be screened to provide around 196 subjects for
      randomization into the study. Assuming an attrition rate of 10% between the baseline visit
      and the six-month treatment visit, this will provide approximately 176 evaluable subjects.
    

Intervention name(s): Ofatumumab 3mg; Ofatumumab 30mg; Ofatumumab 60mg; Placebo
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 3mg of investigational product; 30mg of investigational product; 60mg of investigational product; Placebo
Intervention MeSH terms: Ofatumumab; Antibodies, Monoclonal
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Relapsing Remitting Multiple Sclerosis; Ofatumumab