Ofatumumab Dose-finding in Relapsing Remitting Multiple Sclerosis (RRMS) Patients

A Double-blind, Randomized, Placebo Controlled, Multicenter, Dose-finding Trial of Ofatumumab in Relapsing Remitting Multiple Sclerosis (RRMS) Patients

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.

The trial consists of two phases, a 48 week treatment period, followed by an individualized treatment period of up to two years.

Patients are treated in cohorts of increasing doses (100 mg, 300 mg and 700 mg) with 12 patients in each dose cohort. Within each cohort patients are randomized asymmetrically in a 2:1 ratio such that eight patients will receive ofatumumab and four patients will receive placebo. After 24 weeks the patients randomized to placebo will be treated with the active dose for the cohort. For blinding purposes, patients randomized to the active dose will be treated with placebo after 24 weeks. Thus, each patient will receive two administrations of trial product with 24 weeks follow-up resulting in a total treatment period of 48 weeks duration. An Independent Data Monitoring Committee (IDMC) will review and evaluate the safety data of each cohort, a minimum of 4 weeks data including the week 4 Magnetic Resonance Imaging (MRI) from at least 10 patients, to consider if progression to the next higher dose cohort is acceptable.

The trial product is administered as two infusions separated by two weeks. Clinical assessment and Gadolinium enhanced (Gd-enhanced) MRI scan will be performed at weeks -4, 0, 2, 4, and every 4 weeks until week 48. The MRI scan at week 2 is carried out for safety assessment prior to administering the second infusion in the first treatment course. When patients in all dose cohorts have been dosed and have had week 4 MRI scans performed, an IDMC will review all available safety data.

After completion of week 48 patients will be followed to monitor B-cell and IgG normalization. B-cell levels will be monitored every 12 weeks until CD19+ cells have returned to baseline level (Visit 3) or normalized level. If the B-cell levels are not normalized after two years the patient should be followed until either the IgG or the B-cell levels are normalized (see Section 9.2.4 for details). During this period Gd-enhanced MRI follow up scans will be performed every 12 weeks to evaluate potential rebound, safety and for Progressive Multifocal Leukoencephalopathy (PML) monitoring.

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.