Tocilizumab

A PHASE II/III, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO ASSESS THE EFFICACY AND SAFETY OF TOCILIZUMAB VERSUS PLACEBO IN PATIENTS WITH SYSTEMIC SCLEROSIS

INCLUSION CRITERIA

Patients must meet the following criteria for study entry:
• Ability and willingness to give written informed consent and comply with the requirements of the study protocol
• Diagnosis of SSc, as defined using the American College of Rheumatology criteria (1980; see Appendix 1)
• Disease duration of ≤ 60 months (defined as time from the first non−Raynaud phenomenon manifestation)
• Age ≥ 18 years at baseline
• ≥ 15 and ≤ 40 mRSS units at the screening visit
• Uninvolved skin at one of the following locations:
Front of the middle region of the thighs
Abdomen except for the 2-inch area directly around the navel
Outer area of the upper arms (if a caregiver is giving the patient injections)
• Active disease defined as at least one A criterion and one B criterion each:

o Criteria A at screening
~Increase ≥ 3 in mRSS units at screening compared with the last visit within previous 1–6 months
~Involvement of one new body area with ≥ 2 mRSS units at screening compared with the last visit within the previous 1–6 months
~Involvement of two new body areas with ≥ 1 mRSS units at screening compared with the last visit within the previous 1–6 months
~Other documentation of worsening skin thickening at screening compared with the last visit within the previous 1–6 months consistent with the progression of skin thickening described in the above criteria using mRSS
~Presence of 1 or more TFRs at screening

o Criteria B at screening
~High-sensitivity CRP ≥ 1 mg/dL
~Electrolyte sedimentation rate (ESR) ≥ 28 mm/hr Platelet count (≥ 330 × 103/μL)

• Treatment with oral corticosteroids (≤ 10 mg/day of prednisone or equivalent) is permitted if the patient is on a stable dose regimen for ≥ 2 weeks prior to and including at baseline
• Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is permitted if the patient is on a stable dose regimen for ≥ 2 weeks prior to and including at baseline.
• ACE inhibitors, calcium-channel blockers, proton-pump inhibitors, and/or oral vasodilators are permitted if the patient is on a stable dose for ≥ 4 weeks prior to and including at baseline.
• If female of childbearing potential, the patient must have a negative pregnancy test at screening and the baseline visit.

EXCLUSION CRITERIA

Patients who meet any of the following criteria will be excluded from study entry:

General Exclusion Criteria

• Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization
• Rheumatic autoimmune disease other than SSc, including but not limited to, RA, systemic lupus erythematosis, mixed connective tissue disorder, polymyositis, dermatomyositis, eosinophilic fasciitis, primary Sjögren syndrome, and eosinophilic myalgia syndrome, as determined by the Principal Investigator
• Skin thickening (scleroderma) limited to areas distal to the elbows or knees at screening

Exclusions Related to Previous or Concomitant Therapy

• Treatment with any investigational agent within ≤ 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) of screening
• Previous treatment with cell-depleting therapies, including investigational agents, including but not limited to, CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19, and anti-CD20
• Previous treatment with chlorambucil, bone marrow transplantation, or total lymphoid irradiation
• Previous treatment with TCZ
• Previous treatment with thalidomide, antithymocyte globulin, plasmapheresis, or extracorporal photopheresis
• Treatment with intra-articular or parenteral corticosteroids within ≤ 4 weeks prior to baseline
• Immunization with a live/attenuated vaccine within ≤ 4 weeks prior to baseline
• Treatment with MTX, hydroxychloroquine, cyclosporine A, azathioprine, mycophenolate mofetil (MMF), rapamycin, colchicine, D-penicillamine, or endothelin-receptor antagonists within ≤ 4 weeks prior to baseline
• Treatment with etanercept within ≤ 2 weeks, infliximab, certolizumab, golimumab, abatacept or adalimumab within ≤ 8 weeks, anakinra within ≤ 1 week prior to baseline
• Treatment with cyclophosphamide within ≤ 6 months prior to baseline

Exclusions Related to General Safety

• History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies
• Evidence of moderately severe concurrent nervous system, renal, endocrine, or GI disease not related to SSc, as determined by the Principal Investigator
• Pulmonary disease with forced vital capacity (FVC) ≤ 50% of predicted or a diffusing capacity of the lung for carbon monoxide (DLCO) (hemoglobin corrected) ≤ 40% of predicted
• Known PAH, as determined by the Principal Investigator
• Evidence of other moderately severe pulmonary disease (e.g., asthma, emphysema), as determined by the Principal Investigator
• Cardiovascular disease with significant arrhythmia, congestive heart failure (New York Heart Association Class II–IV), unstable angina, uncontrolled hypertension, cor pulmonale, or symptomatic pericardial effusion
• Current liver disease, as determined by the Principal Investigator
• History of diverticulitis, diverticulosis requiring antibiotic treatment, or chronic ulcerative lower GI disease, such as Crohn’s disease, ulcerative colitis, or other symptomatic lower GI conditions that might predispose a patient to perforations
• Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or other infections (including but not limited to tuberculosis [TB] and atypical mycobacterial disease, hepatitis B and C, and herpes zoster, but excluding fungal infections of the nail beds)
• Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening
• Active 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 treatment (see Appendix 2). Patients treated for TB with no recurrence within 3 years are eligible.
• Primary or secondary immunodeficiency (history of or currently active)
• Evidence of malignant disease, or malignancies diagnosed within the previous 5 years (except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that have been excised and cured)
• Patients with reproductive potential not willing to use an effective method of contraception, such as oral, injected, or implanted hormonal methods of contraception, intrauterine device or intrauterine system, condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam, gel, film, cream, suppository, male sterilization, or true abstinence
• History of alcohol, drug, or chemical abuse within 1 year prior to screening
• Neuropathies or other conditions that might interfere with pain evaluation, as determined by the Principal Investigator
• Body weight > 150 kg

Laboratory Exclusions (at Screening)

• GFR < 60 mL/min
• ALT or AST > 1.5 × the upper limit of normal (ULN)
• Total bilirubin greater than the ULN
• Platelet count < 100 × 109/L (100,000/mm3)
• Hemoglobin < 85 g/L (8.5 g/dL; 5.3 mmol/L)
• WBC < 3.0 × 109/L (3000/mm3)
• ANC < 2.0 × 109/L (2000/mm3)
• Absolute lymphocyte count < 0.5 × 109/L (500/mm3)
• Positive hepatitis B surface antigen (HBsAg) or hepatitis C antibody