Clinical phase I/IIA study of subcutaneous administration of Ofatumumab in Rheumatoid Arthritis patients on stable dose Methotrexate

Active, not recruiting

Conditions: Rheumatoid Arthritis
MedDRA version: 9.1Level: LLTClassification code 10039073Term: Rheumatoid arthritis

Registration Number: EUCTR2008-002046-27-BE

Lead Sponsor: GlaxoSmithKline Research & Development Ltd

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Not Recruiting

Sex: All

Target Recruitment: 35

Inclusion Criteria

1. Male or female aged = 18 years.
2. A diagnosis of rheumatoid arthritis according to the American College of Rheumatology (ACR1987 classification) of at least six months duration from diagnosis at screening.
3. Subjects must be treated with MTX, 7.5-25 mg/week, for at least 12 weeks prior to Visit 2 (study day 1), within the last 4 weeks prior to Visit 2 (study day 1), at a stable dosage.
4. Patient must be willing to receive folic acid=5mg/week starting 4 weeks prior to baseline (Visit 2) until the last visit administered according to local practice.
5. Body mass index (BMI) < 35kg/m2 (inclusive).
6. A female subject is eligible to participate if she is of child-bearing potential and agrees to use one of the contraception methods listed in Section 8.1 for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until one year after the last dose of Ofatumumab.
7. Male subjects must agree to use one of the contraception methods listed in Section 8.1. This criterion must be followed from the time of the first dose of study medication until after completion or withdrawal from study following advice of physician prescribing MTX and in accordance with local methotrexate label.
8. QTcB or QTcF < 450 msec.
9. Chest x-ray is negative for any finding associated with an acute or chronic lung infection at screening.
A chest X-ray with postero-anterior projections and, if indicated, lateral projections, taken within 12 weeks prior to Visit 1, may be used. Only if clinically warranted should the x-ray be repeated at screening.
10. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
11. Following receipt of verbal and written information about the study, the subject must provide signed informed consent before any study related activity including wash-out of other drug products is carried out.
France: 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.

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion Criteria

1. 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).
2. 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.
3. Exposure to etanercept < 4 weeks, infliximab or adalimumab < 8 weeks, or abatacept or anakinra < 12 weeks prior to visit 2.
4. 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 corticosteorids
• Live/attenuated vaccinations
• Cyclosporine
• Azathioprine
• Penicillamine
• Sulfasalazine
• Bucillamine
• Hydroxychloroquine
• Chloroquine
5. Exposure to leflunomide within 12 weeks prior to Visit 2 unless the patient has completed peroral cholestyramine treatment for washout according to manufacturer's instructions and locally accepted clinical practices.
6. Exposure to gold therapy = 12 weeks prior to Visit 2.
7. Exposure to IV immunogammaglobulins = 24 weeks prior to Visit 2
8. Past or current malignant melanoma.
9. Past or current malignancy, except for:
• Cervical carcinoma Stage 1B or less
• Non-invasive basal cell skin carcinoma
• Other cancer with a complete response duration of > 5 years
10. 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.
• Screening for TB will be done in accordance with local guidelines including Mantoux testing, and if necessary follow-up with QuantiFERON testing for patients whose history of immunization with BCG cannot be documented.
• Patients with a negative test OR a positive Mantoux test and a negative QFT-G test are eligible for inclusion into the study.
• Patients with a positive Mantoux test without QFT-G negativity are excluded. Additionally, patients with documented BCG vaccination will be exempted from the Mantoux test assessment.
11. Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months from screening, congestive heart failure, known QT abnormalities, and arrhythmia requiring therapy, with the exception of extra systoles or minor conduction abnormalities.
12. Significant concurrent, uncontrolled medical condition including, but not limited to, PML, renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral psychiatric disease, or evidence of demyelinating disease.
13. History of significant cerebrovascular disease.
14. Known HIV positive.
15. Screening laboratory values (according to central laboratory):
• Hemoglobin < 5.6 mmol/L (9.0 g/dL)
• CD19+ B-cell count < 0.1 x 109/L
• Neutrophils < 2 x 109/ L
• Platelets < 100 x 109/ L
• Serum IgG < lower limit of normal
• S-ALAT > 3 times the upper limit of normal
• S-AST > 3 times the upper limit of normal
• S-ALP > 2 times the upper limit of normal
• S-creatinine > 133 µmol/L (1.5 mg/dL)
16. Positive serology for hepatitis B (HB) defined as:
• Positive test for HBsAg.
If negative, Hep B serology negativity will be confirmed by:
• Negativ

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To characterize the safety & tolerability of ofatumumab administered as a single subcut dose in patients with rheumatoid arthritis.<br>;Primary end point(s): • Safety and tolerability as described by the incidence and severity of adverse events [AEs], clinical laboratory parameters and vital signs.<br>;Secondary Objective: 1) To identify and characterize requirement for pre-medication with systemic steroids in association with subcut ofatumumab in patients with rheumatoid arthritis.<br>2) To explore the pharmacodynamic dose-response curve for subcut ofatumumab.<br>3) To determine the minimum dose of ofatumumab that results in target level of depletion of peripheral blood B- lymphocytes after single subcut. administration. Target level is defined as >95% or to below LLQ, as measured by change from baseline at week 4 and/or the median value across weeks 2-4.<br>4) To characterize the PK/PD relationship following single subcut. dose of ofatumumab.<br>

Secondary Outcome Measures

Name	Time	Method

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