Ofatumumab Dose-finding in Relapsing Remitting Multiple Sclerosis (RRMS) Patients
Condition: Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis
Intervention: Ofatumumab 100; Ofatumumab 300; Ofatumumab 700; Placebo
Intervention description: 100mg; 300mg; 700mg; matching placebo
Intervention MeSH terms: Ofatumumab; Antibodies, Monoclonal
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 38.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: No
Keywords: relapsing forms of multiple sclerosis; ofatumumab; multiple sclerosis

Summary:

      The trial consists of a dose escalation, to establish the safety of ofatumumab in RRMS
      patients. A 48-week treatment period followed by an individualized follow-up period until
      normalization of peripheral B-cell counts or Immunoglobulin G (IgG) levels.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Patients with definite diagnosis of relapsing-remitting MS according to McDonald
             criteria

          -  Patients with:

          -  At least two confirmed relapses within the last 24 months or

          -  At least one confirmed relapse within the last 12 months or

          -  One confirmed relapse between 12 and 24 months prior to screening, and at least one
             documented T1 Gd-enhancing lesion on an MRI performed within 12 months prior to
             screening.

          -  Patients with disability equivalent to Expanded Disability Status Scale (EDSS) score
             of 0-5.0 (both included) at screening

          -  Neurologically stable patients with no evidence of relapse for at least 30 days prior
             to start of Screening and during the Screening Phase

          -  Female patients must be either post-menopausal, surgically incapable of bearing
             children or practicing an acceptable method of birth control e.g. hormonal
             contraceptives, intrauterine device, spermicide and barrier as long as they are on
             trial medication and for a period of 1 year following the last infusion of trial drug.
             Females of childbearing potential must have a negative pregnancy test at screening
             visit prior to entry into the treatment period

          -  Following receipt of verbal and written information about the trial, the patient must
             provide signed informed consent before any trial related activity is carried out.

        Exclusion Criteria:

          -  Diagnosis of Secondary Progressive Multiple Sclerosis (SPMS), Primary Progressive
             Multiple Sclerosis (PPMS) or Progressive Relapsing Multiple Sclerosis (PRMS) or
             Neuromyelitis optica

          -  Neurological findings consistent with Progressive Multifocal Leukoencephalopathy (PML)
             or confirmed PML

          -  Findings on brain MRI scan indicating any other clinically significant brain
             abnormality other than MS

          -  Patients unable to undergo MRI scans (e.g. due to pacemaker, severe claustrophobia,
             hypersensitivity to contrast media) or who lack adequate peripheral venous access

          -  Patients who have had the following treatments:

          -  Lymphocyte-depleting therapies (e.g. alemtuzumab (Campath®), anti-Cluster of
             Differentiation (CD4), cladribine, total body irradiation, bone marrow
             transplantation), mitoxantrone or cyclophosphamide at any time

          -  Anti-CD20 treatments or any monoclonal antibodies at any time

          -  Immunoglobulin, azathioprine, cyclosporine, tacrolimus or other immunosuppressive
             agents, immunomodulatory agents or plasma exchange within six months prior to
             randomization in the trial apart from Glatiramer Acetate and Interferon Beta (IFN-b).

          -  Glatiramer Acetate or IFN-b within three months prior to the randomization in the
             trial.

          -  Glucocorticoids or Adrenocorticotropic Hormone (ACTH) within one month prior to the
             screening in the trial.

          -  Receipt of a live vaccine within one month prior to screening in the trial.

          -  Plasmapheresis for treatment of relapses within 2 months prior to randomization in the
             trial.

          -  Initiation of therapy with Statins or hormone replacement treatment within one month
             or less prior to screening in the trial.

          -  Patients who have received other disease modifying therapies for MS may be allowed on
             a case to case basis after discussion with the sponsors medical monitor

          -  Past or current history of medically significant adverse effects (including allergic
             reactions) from:

          -  Cetirizine

          -  Prednisolone

          -  Paracetamol/acetaminophen

          -  Plasma proteins or a known hypersensitivity to components of the investigational
             product.

          -  Past or current malignancy, except for

          -  Cervical carcinoma Stage 1B or less

          -  Non-invasive basal cell and squamous cell skin carcinoma

          -  Cancer diagnoses with a complete response of a duration of > 5 years. Patients with a
             prior history of hematological malignancies are excluded regardless of response

          -  Clinically significant cardiac disease, including acute myocardial infarction within
             six months from screening, unstable angina, congestive heart failure, previous venous
             or arterial thrombosis or arrhythmia requiring therapy.

          -  Electrocardiogram (ECG) showing significant abnormality that the treating investigator
             determines may jeopardize the subject's health (i.e. acute ischemia, left bundle
             branch or bifascicular block)

          -  Significant concurrent, uncontrolled medical condition including, but not limited to,
             renal, hepatic, hematological, gastrointestinal, endocrine, immunodeficiency syndrome,
             pulmonary, cerebral, psychiatric or neurological disease which may impair their
             reliable participation in the trial or necessitate the use of medication not allowed
             by this protocol.

          -  History of severe, clinically significant Central Nervous System (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 systemic treatment such as, but
             not limited to, chronic renal infection, chronic chest infection with bronchiectasis,
             tuberculosis and active Hepatitis C. Any previous serious infections should be
             discussed with the sponsors medical monitor (e.g. opportunistic or atypical
             infections)

          -  Female patients who are pregnant or nursing.

          -  Use of an investigational drug or other experimental therapy for a condition other
             than MS within 4 weeks prior to screening. Any prior use of an investigational drug or
             other experimental therapy for MS at any time should be discussed with the medical
             monitor.

          -  Current participation in any other interventional clinical trial. Participation in
             non-interventional trial requires approval of the protocol by the sponsor

          -  Serum vitamin B12 below lower limit of normal

          -  Positive polymerase chain reaction (PCR) screening for John Cunningham Virus (JC
             Virus) as measured by qualitative plasma and/or white blood cell JCV DNA

          -  Serologic evidence of Hepatitis B (HB) infection based on the results of testing for
             Hepatitis B Surface Antigen (HBsAg), anti- Hepatitis B Core (HBc) and anti- Hepatitis
             B Surface (HBs) antibodies with eligibility based on the results as follows:

          -  Patients positive for HBsAg are excluded

          -  Patients negative for HBsAg but positive for both anti-HBc and anti-HBs antibodies
             (indicating past infection) are eligible

          -  Patients negative for HBsAg and anti-HBc antibody but positive for anti-HBs antibody
             (indicating past vaccination) are eligible

          -  Patients negative for HBsAg and anti-HBs antibody but positive for anti-HBc antibody
             will require clarification of their status by testing for HB DNA, which if positive
             will exclude the patient from participation

          -  Patient with documented vaccination against Hepatitis B (primary and secondary
             immunization and booster) will be considered eligible for the trial.

          -  Positive serology for HIV

          -  Screening laboratory values:

          -  White Blood Cell (WBC) < 3.0 x 109/L

          -  Neutrophils < 2 x 109/L

          -  Platelets < 100 x 109/L

          -  Circulating IgG level < lower limit of normal (according to central laboratory range)

          -  Serum Alanine Aminotransferase (S-ALAT) > 2.5 times the upper limit of normal
             (according to central laboratory range)

          -  Serum Alpha Fetoprotein (S-AP) > 2.0 times the upper limit of normal (according to
             central laboratory range)

          -  Serum Aspartate Aminotransferase (ASAT) >3.0 times the upper limit of normal
             (according to central laboratory range)

          -  Bilirubin > 1.5 times the upper limit of normal (according to central laboratory
             range)

          -  S-creatinine > the upper limit of normal (according to central laboratory range)

          -  CD4 count <500 cells/mm3, CD4:CD8 <0.9

          -  Patients known or suspected of not being able to comply with a trial protocol (e.g.
             due to alcoholism, drug dependency or psychological disorder).

          -  Positive test for Hepatitis C antibody confirmed with a Hepatitis C real time (RT) PCR
             assay.

        Patients who are positive for Hepatitis C antibody and negative when the Hepatitis C RT PCR
        assay is performed will be eligible for the study. Patients who are positive for Hepatitis
        C antibody and have a positive or indeterminate result when the Hepatitis C RT PCR assay is
        performed will not be eligible for the study.

          -  Positive test results for tuberculosis using the QuantiFERON test and/or Chest X-ray
             findings suggestive of tuberculosis (TB). For patients who have had a Chest X-ray
             performed within the past 6 months without any findings indicative of TB, QuantiFERON
             test alone may be performed.