Musculoskeletal Ultrasound in Predicting Early Dose Titration With Tocilizumab

This is a 24-week, double blind open label clinical trial study to evaluate 57 active Rheumatoid Arthritis (RA) patients who have moderate to severe disease activity with total Power Doppler Ultrasound (PDUS) >10 of 34 joints evaluated by Ultrasound (US) (at screening to enter into the study). All patients will begin treatment with tocilizumab at a dose of 4mg/kg. Two study sites will recruit patients (UCLA and UF) using the same protocol, after standardizing US acquisition methods, as well as scoring. US synovitis scores will be acquired at screening, baseline, and pre-infusion at 4, 12, 16, and 24 weeks, to be able to determine whether change in pre-infusion synovitis score at 4 weeks can be used to predict change in disease activity at 12 weeks. This will provide evidence to whether such reading is useful in predicting which patients may require escalation of dose from 4 to 8 mg/kg. At 12 weeks, patients not meeting low disease activity within the 4mg/kg (disease activity score DAS28/ Erythrocyte Sedimentation Rate (ESR)-4item<3.2) will increase the tocilizumab dose to 8mg/kg (maximum dose 800mg) in a blinded manner to enable evaluation of these US-focused objectives in the context of the current FDA-approved label. The ultrasound scorer will not know information about patient's disease activity (Tender Joint Count (TJC), Swollen Joint Count (SJC), labs etc) or if there was dose escalation at 12 weeks. The clinical assessor of disease activity will be blinded to the ultrasound scores. Additionally, the patient will also be blinded to dose escalation. If patients in the 4mg/kg arm achieve DAS28<3.2 at 12 weeks, patients will continue with their current dose for the duration of the study. Please see the below Table for details on the blinding plan.

Inclusion criteria

Patients must have rheumatoid arthritis. Patients will be included in the trial based on the following criteria:

• Patient must meet 1987 American College of Rheumatology (ACR) criteria,
• Age > 18 years of age,
• Baseline DAS28/ESR>4.4,
• Stable concomitant DMARDs for more than 1 month (methotrexate, leflunomide, plaquenil, sulfasalazine, or no DMARDs). However, if the patient is not on DMARD, history of DMARD use required.

• If not on DMARD (and the patient satisfies the above statement), the patient can opt for monotherapy with tocilizumab or combination therapy OR
• If on biologic monotherapy, can opt for monotherapy with tocilizumab or DMARD combination therapy (ie. patients cannot be on biologic with TCZ)

• Power Doppler score of >10 at screening.

General Medical Concerns:

• Normal organ function, except if abnormal due to the disease under investigation
• Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for six months after completion of treatment.
• Subject has provided written informed consent.

Exclusion criteria

A patient will be excluded if the answer to any of the following statements is "yes".

General:

• Major surgery (including joint surgery) within 8 weeks prior to baseline or planned major surgery within 6 months after baseline.

Excluded Previous or Concomitant Therapy:

• Treatment with any investigational agent within 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) of baseline.
• Previous treatment with any cell-depleting therapies, including investigational agents or approved therapies, some examples are CAMPATH, anti-CD4, anti-CD5, anti-CD3.
• Previous treatment with anti-CD19 and anti-CD20 within 6 months of start of the study.
• Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column within 6 months of baseline.
• Immunization with a live/attenuated vaccine within 4 weeks prior to baseline.
• Previous treatment with TCZ.
• Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation.
• Use of prednisone > 10mg at baseline.

Exclusions for General Safety:

• History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies.
• Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (include uncontrolled diabetes mellitus) or gastrointestinal disease (including complicated diverticulitis, ulcerative colitis, or Crohn's disease.)
• Current liver disease as determined by principal investigator unless related to primary disease under investigation
• Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections (including but not limited to tuberculosis and atypical mycobacterial disease, Hepatitis B and C, and herpes zoster, but excluding fungal infections of nail beds).
• Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of baseline or oral antibiotics within 2 weeks prior to baseline.
• Active Tuberculosis (TB) requiring treatment within the previous 3 years. Patients should be screened for latent TB and, if positive, treated following local practice guidelines prior to initiating TCZ. Patients treated for tuberculosis with no recurrence in 3 years are permitted.
• Primary or secondary immunodeficiency (history of or currently active) unless related to primary disease under investigation.
• Evidence of active malignant disease, malignancies diagnosed within the previous 5 years (including hematological malignancies and solid tumors, except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that has been excised and cured), or breast cancer diagnosed within the previous 5 years.
• Pregnant women or nursing (breast feeding) mothers.
• Patients with reproductive potential not willing to use an effective method of contraception.
• History of alcohol, drug or chemical abuse within 1 year prior to screening.
• Neuropathies or other conditions that might interfere with pain evaluation unless related to primary disease under investigation.
• Patients with lack of peripheral venous access.
• Body weight of > 150 kg.

Laboratory Exclusion criteria (at screening):

• Serum creatinine > 1.6 mg/dL (141 µmol/L) in female patients and > 1.9 mg/dL (168 µmol/L) in male patients. Patients with serum creatinine values exceeding limits may be eligible for the study if their estimated glomerular filtration rates (GFR) are >30.
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 times upper limit of normal (ULN)
• Total Bilirubin > ULN
• Platelet count < 100 x 109/L (100,000/mm3)
• Hemoglobin < 85 g/L (8.5 g/dL; 5.3 mmol/L)
• White Blood Cells < 3.0 x 109/L (3000/mm3)
• Absolute Neutrophil Count < 2.0 x 109/L (2000/mm3)
• Absolute Lymphocyte Count < 0.5 x 109/L (500/mm3)
• Positive Hepatitis BsAg, or Hepatitis C antibody
• HIV positive