PK, PD, Safety, and Efficacy of SAIT101 Versus MabThera® Versus Rituxan® in Patients With Rheumatoid Arthritis
Condition: Rheumatoid Arthritis
MeSH terms: Arthritis; Arthritis, Rheumatoid
Intervention: SAIT101; MabThera; Rituxan
Intervention description: 1,000 mg i.v. of SAIT101 on Day 1 and 15. 1,000 mg i.v. of SAIT101 on week 24 and 26 for eligible patients.; 1,000 mg i.v. of MabThera® on Day 1 and 15. 1,000 mg i.v. of MabThera® on week 24 and 26 for eligible patients.; 1,000 mg i.v. of Rituxan® on Day 1 and 15. 1,000 mg i.v. of Rituxan® on week 24 and 26 for eligible patients.
Intervention MeSH terms: Rituximab
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: In Part A, patients are randomized in a 1:1:1 ratio to receive one course (baseline and Week 2) of SAIT101 (n=94) versus Rituxan® (n=94) versus MabThera® (n=94).
At Week 24, patients are evaluated for the second course (Week 24 and 26) of the infusion.
In Part B, eligible patients in the SAIT101 arm receive the second course of SAIT101 treatment. Eligible patients in the MabThera® arm receive the second course of MabThera® treatment. Eligible patients in the Rituxan® arm are randomized in a 1:1 ratio to receive SAIT101 or Rituxan® treatment. Patients are followed up for safety until Week 52.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 294.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: an inadequate response to anti -TNF therapy

Summary:

      A randomised, double blind, parallel group, multicentre study yo compare the
      pharmacokinetics, pharmacokinetics, safety and efficacy of SAIT101 versus MabThera® versus
      Rituxan® in patients with rheumatoid arthritis.
    

Eligibility criteria:

        Inclusion Criteria:

        1. 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.

             2. 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).

             3. 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:

          1. Females who are pregnant, breastfeeding, or planning a pregnancy during the Treatment
             Period of and 12 months after the last infusion of study drug.

          2. 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.

          3. 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).

          4. 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.

          5. Primary or secondary immunodeficiency (history of, or currently active), including
             known history of human immunodeficiency virus (HIV) infection or positive test at
             screening.

          6. History of opportunistic infection.

          7. History of deep space/tissue infection (e.g., fasciitis, abscess, osteomyelitis) and
             infected prosthetic joint.

          8. 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

          9. 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).

         10. 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.

         11. 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).

         12. 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.

         13. 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.

         14. 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.

         15. Hypogammaglobulinemia at screening (Immunoglobulin G (IgG) <600 mg/dL).

         16. 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.

        18. 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).

        19. 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.

        20. 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.

        21. Injectable corticosteroids within 6 weeks prior to Day 1.

        22. 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.

        23. 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).

        24. Patients who, in the judgment of the Investigator, are likely to be non-compliant or
        uncooperative during the study.

        25. History of substance abuse (alcohol or drug).

        26. History of demyelinating disorders (such as multiple sclerosis or Guillain-Barré
        syndrome).

        27. 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)