PK, PD, Safety, and Efficacy of SAIT101 Versus MabThera® Versus Rituxan® in Patients With Rheumatoid Arthritis

This is a randomized, double-blind, parallel group, multicenter study to compare the pharmacokinetics (PK), pharmacodynamics (PD), safety, efficacy, tolerability, and immunogenicity of SAIT101 (biosimilar rituximab) versus MabThera® versus Rituxan® in patients with rheumatoid arthritis (RA). This study will take place globally across approximately 75 study centers in order to randomize approximately 282 patients. The study consists of Part A from baseline for PK and efficacy analysis, followed by Part B from Week 24 to 52 for safety follow-up in which collects transition data.

Inclusion criteria

• Severe RA defined as:

• Diagnosis of RA according to the revised (1987) American College of Rheumatology (ACR) criteria for the classification of RA for at least 3 months prior to screening visit (see Appendix 3).
• And ≥6 swollen joints and ≥6 tender/painful joints (from the 66/68 joint count system).
• And C-reactive protein (CRP) ≥1.0 mg/dL or an erythrocyte sedimentation rate (ESR) ≥28 mm/hour at Screening.
• And positive rheumatoid factor (RF) (≥20 units/mL) or anti cyclic citrullinase peptide (CCP) antibodies (≥10 units/mL) at Screening.

• Patients with severe RA who have had an inadequate response to at least 3 months' treatment (according to the approved treatment and dosage) or intolerance (at Investigator's discretion and/or experience of intolerable AE or toxicity such as infusion related reaction, hypersensitivity, anaphylaxis or severe toxicity) to anti-tumour necrosis factor (TNF) therapy (experience of severe adverse event (AE) or toxicity).

• Current treatment for RA on an outpatient basis:
• Receiving methotrexate (MTX) 7.5 - 25mg/week (oral or parenteral) for at least 12 weeks, including the last 4 weeks prior to Day 1 at a stable dose, via the same route of administration, dose, and formulation. Patients receiving a lower dose of MTX (<10 mg/week), stable for 4 weeks prior to Day 1, should be doing so as a result of a documented evidence of intolerance to higher doses of MTX.

Exclusion criteria

• Females who are pregnant, breastfeeding, or planning a pregnancy during the Treatment Period of and 12 months after the last infusion of study drug.
• Class IV as per the Classification of Global Functional Status in Rheumatoid Arthritis (as per ACR 1991 Revised Criteria) (see Appendix 4) or wheelchair/bed bound.
• History of or current inflammatory joint disease other than RA (including but not limited to gout, reactive arthritis, psoriatic arthritis, seronegative spondyloarthropathy or Lyme disease).
• History of or current systemic autoimmune disorder (including but not limited to systemic lupus erythematosus, inflammatory bowel disease, pulmonary fibrosis, Felty syndrome, scleroderma, inflammatory myopathy, fibromyalgia, juvenile idiopathic arthritis, mixed connective tissue disease, vasculitis or other overlap syndrome), with the exception of the secondary Sjögren's syndrome.
• Primary or secondary immunodeficiency (history of, or currently active), including known history of human immunodeficiency virus (HIV) infection or positive test at screening.
• History of opportunistic infection.
• History of deep space/tissue infection (e.g., fasciitis, abscess, osteomyelitis) and infected prosthetic joint.
• Active infection of any kind (excluding fungal infection of nail beds) or any major episode of infection requiring hospitalization or treatment with i.v. anti infective agents within 4 weeks prior to Screening or oral anti-infective agents within 2 weeks prior to Screening or use of antibiotic therapy three or more times in the last six months prior to Screening
• Positive serological test for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb) or hepatitis C serology.

• Patients with a negative HBsAg and positive HBcAb must have a hepatitis B virus (HBV) deoxyribonucleic acid (DNA) level <20 IU/mL (or 112 copies/mL) by polymerase chain reaction (PCR). These HBV patients must be willing to undergo monthly PCR HBV DNA testing during treatment and may participate following consultation with a hepatitis expert regarding monitoring and use of HBV antiviral therapy, and provided they agree to receive treatment as indicated. An HBV re-test will be performed monthly including Day 1, Weeks 4, 8, 12, 16, 20, 24, 36, 52, and unscheduled visit if required.
• Patients with a positive test because of HBV vaccine may be included (i.e., anti-HBs+ and anti HBc-).
• Patients positive for hepatitis C virus (HCV) antibody are eligible only if PCR is negative for HCV ribonucleic acid (RNA).
• Confirmed current active tuberculosis (TB). • Patients with latent TB as determined by positive QuantiFERON-TB test may be enrolled if such patients have written confirmation from health care provider (e.g., Pulmonologist or Infection Specialist) of adequate prophylaxis before or within the screening period and no evidence of tuberculosis on a chest X-ray performed within 3 months from Day 1.

• Screening period can be extended to 60 days for prophylaxis of latent TB.

• QuantiFERON-TB test can be re-tested, if inconclusive.
• Any significant cardiac disease (e.g., coronary artery disease with unstable angina, coronary heart failure New York Heart Association Class III and IV, familial long QT syndrome, uncontrolled cardiac disease).
• History of moderate to severe chronic obstructive pulmonary disease (COPD) and/or history of severe COPD exacerbation(s) within the last 12 months of Screening.
• Vaccination with live or attenuated vaccines within 6 weeks prior to first dose of study drug or planned administration during study participation or within 4 weeks following last dose of study drug. Treatment with IV Gamma Globulin or the Prosorba® Column within 6 months prior to Day 1.
• History of a severe allergic reaction or anaphylactic reaction to a biological agent or history of hypersensitivity to any component of the study drug including known hypersensitivity or allergy to a murine product.
• Hypogammaglobulinemia at screening (Immunoglobulin G (IgG) <600 mg/dL).
• Patients with hemoglobin <8.5 g/dL, absolute neutrophil count (ANC) <1,500 cells/µL or platelet count <75,000 cells/µL at Screening. If a patient has findings marginally below this limit, re testing is allowed, at the Investigator's discretion, within the 30 day period between Visit 1 and Visit 2.

• Creatinine clearance < 50 mL/min (Cockcroft-Gault formula)

• Liver function: Total bilirubin >2.0 mg/dL (>34 µmol/L) except for patients with Gilbert's Syndrome or hemolysis. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >3 × upper limit of normal (ULN). Patients with total bilirubin >2.0 mg/dL possibly due to Gilbert's Syndrome should have a direct bilirubin checked. If the direct bilirubin is normal and medical history is suggestive/positive for Gilbert's Syndrome, the patient successfully meets the criteria.

The AST and ALT may be repeated once within the Screening period if the initial result exceeds this limit, and the lesser value accepted if it meets this criterion.

• History of cancer within the last 5 years prior to Screening, treated with anti-cancer chemotherapy, including solid tumors and hematologic malignancies and carcinoma in situ (except basal cell and squamous cell carcinomas of the skin or carcinoma in situ of the cervix uteri that have been excised and cured).

• Major surgical procedure within 4 weeks prior to or planned within 24 weeks of Day 1, with the exception of surgical procedures for dental prosthesis.

• Previous treatment with a B cell modulating or B cell depletion therapy, such as, but not limited to rituximab, belimumab, atacicept, tabalumab, ocrelizumab, ofatumumab, obinutuzumab, epratuzumab and other experimental treatments.

• Injectable corticosteroids within 6 weeks prior to Day 1.

• Participation in a previous clinical study within 4 weeks of Screening or having received treatment with a drug that has not received regulatory approval for any indication within a minimum of 5 half-lives prior to Day 1.

• Patients who, based on the Investigator's judgment, have a clinically significant or unstable medical or surgical condition that may preclude safe and complete study participation. Conditions may also include cardiovascular, vascular, pulmonary, hepatic, renal, endocrine or neurological conditions as determined by medical history, physical examination, laboratory tests or electrocardiogram (ECG).

• Patients who, in the judgment of the Investigator, are likely to be non-compliant or uncooperative during the study.

• History of substance abuse (alcohol or drug).

• History of demyelinating disorders (such as multiple sclerosis or Guillain-Barré syndrome).

• Patients at risk of progressive multifocal leukoencephalopathy (PML):

• Patients with immune deficiency such as transplant patients on immunosuppressive medications
• Patients receiving certain kinds of chemotherapy
• Patients receiving natalizumab (Tysabri®) for multiple sclerosis
• Patients with psoriasis on longer term efalizumab (Raptiva®) or patients with acquired immunodeficiency syndrome (AIDS)