Ofatumumab Subcutaneous Administration in Subjects With Relapsing-Remitting Multiple Sclerosis
Condition: Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis
Intervention: Ofatumumab 3mg; Ofatumumab 30mg; Ofatumumab 60mg; Placebo
Intervention description: 3mg of investigational product; 30mg of investigational product; 60mg of investigational product; Placebo
Intervention MeSH terms: Ofatumumab; Antibodies, Monoclonal
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 232.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: No
Keywords: Relapsing Remitting Multiple Sclerosis; Ofatumumab

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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Able to provide signed, written informed consent to participate in the study

          -  18-55 years of age.

          -  Definite diagnosis of MS according to the 2010 revisions of the McDonald diagnostic
             criteria for MS [Polman, 2011].

          -  Subjects do not have any manifestation of another type of MS other than RRMS.

          -  Subjects must have a relapsing-remitting course of disease with at least one of the
             following prior to screening:

          -  At least one confirmed relapse within the previous year or

          -  At least two confirmed relapses within the previous 2 years or

          -  At least one relapse in the previous 2 years, with a GdE brain lesion on an MRI scan
             in the past year.

          -  Expanded Disability Status Scale (EDSS) score of 0-5.5 (inclusive) at screening.

          -  Neurologically stable with no evidence of relapse for at least 30 days prior to start
             of Screening and during the Screening Phase (subjects who relapse during the screening
             Phase can be re-screened, once the relapse has resolved).

          -  A female subject is eligible to enter the study if she is:

          -  Of non-childbearing potential

          -  Of childbearing potential and NOT pregnant or nursing, has a negative serum pregnancy
             test at screening, and agrees to one of the following:

          -  Complete abstinence from intercourse for the period from consent into the study until
             6 months after the last dose of investigational product; or,

          -  Consistent and correct use of one of the following acceptable methods of birth control
             for the period from consent into the study until 6 months after the last dose of
             investigational product:

        Oral contraceptives (either combined or progesterone only) Injectable progesterone
        Levonorgestrel implants Estrogenic vaginal ring Percutaneous contraceptive patches
        Intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of
        <1% per year Male partner sterilization (vasectomy with documentation of azoospermia) prior
        to the female subject's entry into the study; this male must be the sole partner for the
        subject Double barrier method: condom and an occlusive cap (diaphragm or cervical/vault
        caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository).

        A female is considered "Non-childbearing potential" if she is status-post hysterectomy,
        status-post surgical removal of both ovaries, has current, documented tubal ligation, or is
        postmenopausal and >2 years without menses. Female subjects who are post-menopausal <2
        years must be confirmed menopausal by Follicle Stimulating Hormone (FSH) and estradiol
        levels.

        A female is considered "childbearing potential" if she has functional ovaries, ducts, and
        uterus with no impairment that would cause sterility. This includes women with
        oligomenorrhea (even severe), and women who are perimenopausal or who have just begun to
        menstruate.

          -  French subjects: In France, a subject will be eligible for inclusion in this study
             only if either affiliated to, or a beneficiary of, a social security category.

        Exclusion Criteria:

          -  Unable to undergo MRI scans (e.g. due to pacemaker, severe claustrophobia,
             hypersensitivity to contrast media, or who lack adequate peripheral venous access).

          -  Any clinically significant brain abnormality other than MS found on MRI.

          -  Neurological findings consistent with Progressive Multifocal Leukoencephalopathy (PML)
             or confirmed PML (see Appendix 4, Section 11.4, for PML monitoring algorithm).

          -  Subjects whom experience a relapse during the Screening Phase. These subjects may be
             eligible for re-screening after consultation with GlaxoSmithKline (GSK).

          -  History of clinically significant Central Nervous System (CNS) trauma (e.g. traumatic
             brain injury, cerebral contusion, spinal cord compression) or a history or presence of
             myelopathy due to spinal cord compression by disk or vertebral disease.

          -  Prior treatment with any of the following:

          -  Systemic glucocorticoids or Adrenocorticotrophic hormone (ACTH) within one month prior
             to screening

          -  Receipt of a live vaccine within 6 weeks prior to screening

          -  Glatiramer acetate (Copaxone) or Interferon (IFN)-β (Betaferon, Betaseron, Avonex, or
             Rebif) within 3 months prior to screening

          -  Any immunomodulatory therapies, excluding glatiramer acetate or IFN-β, within 6 months
             prior to screening including natalizumab and fingolimod (Gilenya), immunoglobulin, or
             plasma exchange/plasmapheresis

          -  Any monoclonal antibodies at any time, other than natalizumab (Tysabri)

          -  Any lymphocyte-depleting therapies, including, but not limited to: cladribine,
             anti-Cluster of Differentiation 4 (CD4), total body irradiation, or bone marrow
             transplantation

          -  Any immunosuppressive agents, including, but not limited to: mitoxantrone,
             azathioprine, cyclosporine, cyclophosphamide, or tacrolimus

          -  Past or current history of medically significant adverse effects (including allergic
             reactions) from:

          -  Cetirizine (or equivalent)

          -  Paracetamol/acetaminophen

          -  Corticosteroids

          -  Known hypersensitivity to components of the investigational product.

          -  Past or current malignancy, except for

          -  Cervical carcinoma Stage 1B (cancer is present but has not spread) or less

          -  Non-invasive basal cell and squamous cell skin carcinoma

          -  Cancer diagnoses with a duration of complete response (remission) >5 years

          -  A history of hematologic malignancy excludes a subject from participation, regardless
             of response.

          -  Electrocardiogram (ECG) showing a clinically significant abnormality at Screening or
             showing an average QT interval for heart rate corrected using Bazett's Formula (QTcB)
             or QT interval for heart rate corrected using Fridericia's Formula (QTcF) interval
             >/=450 msec (>/=480 msec for subjects with a Bundle Branch Block) over 3 consecutive
             ECGs.

          -  Significant concurrent, uncontrolled medical condition including, but not limited to,
             cardiac, renal, hepatic, hematological, gastrointestinal, endocrine, immunodeficiency
             syndrome, pulmonary, cerebral, psychiatric, or neurological disease which in the
             opinion of the investigator could affect the subject's safety, impair the subject's
             reliable participation in the trial, impair the evaluation of endpoints, or
             necessitate the use of medication not allowed by this protocol.

          -  History of severe, clinically significant CNS trauma (e.g. cerebral contusion, spinal
             cord compression) or a history or presence of myelopathy due to spinal cord
             compression by disk or vertebral disease.

          -  Chronic or ongoing active infectious disease requiring long term systemic treatment
             such as, but not limited to, chronic renal infection, chronic chest infection with
             bronchiectasis, tuberculosis, or active hepatitis C.

          -  Previous serious opportunistic or atypical infections.

          -  Positive polymerase chain reaction (PCR) screening for John Cunningham (JC) Virus as
             measured by plasma John Cunningham Virus (JCV) DNA.

          -  Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In
             addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HB
             DNA test will be performed and if positive the subject will be excluded.

          -  Prior history, or suspicion, of tuberculosis (TB)

          -  Known history of positive serology for HIV.

          -  Any of the following screening laboratory values:

          -  White blood cells (WBC) <3.8 GI/L.

          -  Neutrophils <2 x 109/L.

          -  Platelets <1.3 x 105 GI/L.

          -  Circulating IgG, Immunoglobulin M (IgM), or Immunoglobulin A (IgA) levels < lower
             limit of normal (according to central laboratory range)

          -  Alanine aminotransferase (ALT) >2.0 times the upper limit of normal

          -  Aspartate aminotransferase (AST) >2.0 times the upper limit of normal

          -  Alkaline phosphatase (ALP) >1.5 times the upper limit of normal

          -  Bilirubin >1.5 times the upper limit of normal

          -  CD4 count <500 cells/mm3.

          -  CD19+ B-lymphocyte counts < lower limit of normal (according to central laboratory
             range)

          -  Creatinine clearance <60 mL/minute (by Cockcroft and Gault).

          -  Subjects known or suspected of not being able to comply with a trial protocol (e.g.
             due to alcoholism, drug dependency or psychological disorder).

          -  A documented history of attempted suicide over the 6 months prior to the screening
             visit, presents with suicidal ideation of type 4 or 5 on the C-Suicide Severity Rating
             Scale (SSRS) at the Screening visit, OR if in the investigator's judgment, the subject
             is at risk for a suicide attempt.

          -  Use of an investigational drug or other experimental therapy for a condition other
             than MS within 4 weeks, 5 pharmacokinetic half lives or duration of biological effect
             (whichever is longer) prior to screening. Any prior use of an investigational drug or
             other experimental therapy for MS at any time should be discussed with the GSK Medical
             Monitor.

          -  Current participation in any other interventional clinical trial. Participation in a
             non-interventional trial requires approval of the protocol by the GSK Medical Monitor

          -  French subjects: the French subject has participated in any study using an
             investigational drug during the previous 30 days