Study to Evaluate SC Route of Administration of Ofatumumab in RA Patients

Study Overview
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Brief Summary
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This study will examine the safety and tolerability, PK and PD of subcutaneously administered GSK1841157 in patients with RA on stable dose Methotrexate. The study comprises a single dose escalation/de-escalation phase to investigate the minimal efficacious dose based on PD markers with an acceptable safety profile.

Official Title
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Clinical Phase I/IIA Study of Subcutaneously Administration of Ofatumumab in Rheumatoid Arthritis Patients on Stable Dose Methotrexate

Conditions
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Arthritis, Rheumatoid

Intervention / Treatment
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* Other: placebo
* Drug: ofatumumab


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male or female aged ≥ 18 years A diagnosis of rheumatoid arthritis according to the American College of Rheumatology (ACR1987 classification) of at least six months prior to screening Subjects must be treated with MTX, 7.5-25 mg/week, for at least 12 weeks prior to Visit 2, with the last 4 weeks prior to Day 2 at a stable dosage Patient must be willing to receive folic acid ≥5mg/wk 4 weeks prior to baseline administered according to locally accepted practice Body mass index (BMI) < 35kg/m2 (inclusive) Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form Key Exclusion Criteria: Subjects with a history of a rheumatic autoimmune disease other than RA (except secondary Sjögren's syndrome), or with significant systemic involvement secondary to RA (vasculitis, pulmonary fibrosis or Felty's syndrome) Previous exposure to biologic cell depleting anti-rheumatic therapies, including investigational compounds (e.g. anti-CD11a, anti-CD19, anti-CD20, anti-CD22, anti-BLyS/BAFF, anti-CD3, anti-CD4, anti-CD5, anti-CD52) Exposure to etanercept < 4 weeks, infliximab or adalimumab < 8 weeks, or abatacept or anakinra < 12 weeks prior to visit 2 Received any of the following treatments within 4 weeks prior to Visit 2: Anti-cancer therapy (e.g. alkylating agents, anti-metabolites, purine analogues, monoclonal antibodies) Glucocorticoid unless given in doses equivalent to ≤ 10 mg of prednisolone /day Intra-articular, i.m. or IV corticosteroids Live/attenuated vaccinations Cyclosporine Azathioprine Penicillamine Sulfasalazine Bucillamine Hydroxychloroquine Chloroquine Exposure to leflunomide within 12 weeks prior to visit 2 unless the subject has completed peroral cholestyramine treatment Exposure to gold therapy ≤ 12 weeks prior to Visit 2 Exposure to IV immunogammaglobulins ≤ 24 weeks prior to Visit 2 Past or current malignant melanoma Chronic or ongoing active infectious disease requiring systemic treatment such as, but not limited to, renal infection, chest infection with bronchiectasis, tuberculosis and active hepatitis B and C History of significant cerebrovascular disease Positive plasma / white cell JC Virus (JCV) PCR (either compartment)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 30mg<br>active | Drug: ofatumumab<br>* fully human anti-CD20 monoclonal antibody<br>|
| Experimental: 3mg<br>active | Drug: ofatumumab<br>* fully human anti-CD20 monoclonal antibody<br>|
| Experimental: 0.3mg<br>active | Drug: ofatumumab<br>* fully human anti-CD20 monoclonal antibody<br>|
| Placebo Comparator: placebo<br>placebo | Other: placebo<br>* placebo<br>|
| Experimental: 60mg<br>60mg | Drug: ofatumumab<br>* fully human anti-CD20 monoclonal antibody<br>|
| Experimental: 100mg<br>100mg | Drug: ofatumumab<br>* fully human anti-CD20 monoclonal antibody<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability as described by the incidence and severity of adverse events [AEs], clinical laboratory parameters and vital signs. |  | throughout the study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Requirement for the use of pre-medication, including the timing, type and dose required. |  | throughout study | 
| Pharmacodynamics (B-cell depletion and re-population) as measured by CD-19 peripheral blood B- lymphocyte count via routine fluorescent activated cell sorting (FACS) analysis. |  | throughout study | 
| PK/PD parameters including estimation of time to re-population of CD-19 peripheral blood B-cells to above LLQ (and/or <95% depletion) following single subcutaneous dose of Ofatumumab. |  | throughout study | 
| Immunogenicity as measured by the incidence, titre and type of human anti-human antibody (HAHA) immune response. |  | throughout study | 
| Other pharmacodynamic/biomarkers of disease activity and immune status may include high sensitivity C-reactive protein (hsCRP), Erythrocyte Sedimentation Rate (ESR), B-Lymphocyte Stimulator (BLyS/BAFF), B-Lymphocyte Chemokine (BLC), IL-6, |  | throughout study | 
| Immunoglobulins (IgA, IgG, IgM), Complement (CH50, C3, C4), IgM Rheumatoid Factor (IgM-RF), IgA-RF and IgG-RF, anti-cyclic citrullinated peptide antibody (aCCP), |  | throughout study | 
| serum amyloid A (SAA), CD-3+, CD-4+ and CD-8+ lymphocytes or other biomarkers, as data permit. |  | throughout study | 
| Pharmacodynamics (B-cell depletion and re-population) as measured by CD-19 peripheral blood B- lymphocyte count via routine FACS analysis.Other Secondary Endpoints |  | throughout study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GSK1841157;, rheumatoid arthritis,, B-cell depletion, anti-CD20 monoclonal antibody,