A Randomized, Double-blind, Placebo-controlled, Parallel-Group, Dose-Ranging Study to Investigate the MRI Efficacy and Safety of Six Months* administration of Ofatumumab in Subjects with Relapsing-Remitting Multiple Sclerosis (RRMS) (OMS112831)

Ofatumumab is a novel monoclonal antibody 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 T1 lesions and the relapse rate in Relapsing-Remitting
Multiple Sclerosis (RRMS).
Ofatumumab is marketed under the trade name Arzerra for the intravenous
treatment of chronic lymphocytic leukemia in patients refractory to fludarabine
and alemtuzumab.
A Phase II study of ofatumumab in RRMS subjects is ongoing. The primary
objective of this study 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 has been completed; there are currently 4
subjects ongoing in the 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 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' CD19+ and CD20+
levels were 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.
The present study will evaluate the MRI efficacy in subjects with RRMS, as well
as continue to investigate the safety, of ofatumumab using a subcutaneous
formulation.

Primary: To determine whether ofatumumab 3, 30 or 60 milligrams (mg) given
subcutaneously (SQ), reduces the cumulative number of new T1 GdE brain lesions
over a period of 12 weeks, as compared with placebo.
Secondary: Cumulative number of new T1 GdE brain lesions over 24 weeks, safety
and tolerability, preliminary assessment of effect on relapses, extent of
B-cell depletion, immunogenicity.

Multicenter randomized double blind phase II dose ranging parallel group study.
Screening 6 weeks, treatment phase 24 weeks, follow-up 24 weeks.
Randomization naar behandeling met:
* Ofatumumab 3 mg s.c. every 12 weeks
* Ofatumumab 30 mg s.c. every 12 weeks
* Ofatumumab 60 mg s.c. every 12 weeks
* Ofatumumab 60 mg s.c. every 4 weeks
* Placebo and 12 weeks thereafter ofatumumab 3 mg s.c. .
1 week prior to start of the treatment phase start dose with ofatumumab 3 mg
s.c. or placebo.
Study duration 54 weeks.
Upon completion or withdrawal from the core study period, subjects whose CD19+
B-cell counts are less than the lower limit of normal or baseline will be
followed in the Individualized Follow-up Phase until recovery of the count.
The Netherlands will not participate in the sub-studies.
Approx. 196 patients (245 to be screened).

Treatment with ofatumumab or placebo.

Risk: Adverse effects of study medication.
Burden: Study duration 54 weeks, possibly plus individualized follow-up
thereafter.

During the 54 weeks:
12-13 visits. Duration 2-8 h.
S.c. injections (1 mL) with study drug or placebo every 4 weeks during the
treatment phase (plus 1 week after start treatment), 7x in total..
Blood draws: approx. 45 mL per occasion, every visit. Optional pharmacogenetic
testing (10 mL blood).
Pregnancy test 12x.
ECG 1x.
Some short tests to assess arm, hand and leg function 10x.
MRI brain (with gadolinium) 9x.
Questionnaires (2) 14x (1 should be answered by telephone). Mental status and
fatigue. Duration 5-10 min.

Individualized follow-up:
Visit every 12 weeks.
Blood draws and questionnaires every visit.