Effect of Subcutaneous ACTEMRA on Inflamed Atherosclerotic Plaques in Patients With Rheumatoid Arthritis
Condition: Rheumatoid Arthritis
MeSH terms: Arthritis; Arthritis, Rheumatoid; Plaque, Atherosclerotic
Intervention: tocilizumab
Intervention description: subjects will be treated with 162mg of weekly subcutaneous tocilizumab in an open-label manner, this will be done addition to MTX or monotherapy. On subsequent weeks after the first dose of tocilizumab, subjects will be instructed to inject the full amount of syringe according to the directions provided in the Instructions For Use (IFU).
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 16.0
Sex: Female
Minimum age: 50 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: tocilizumab; subcutaneous injection; rheumatoid arthritis; plaque inflammation; atherosclerotic plaque; joint inflammation; FDG-PET; PET-MR; ACTEMRA

Summary:

      The purpose of this study is to test the hypothesis that anti-IL-6 therapy is effective for
      reducing plaque inflammation as measured by fluorine-2-deoxy-D-glucose positron emission
      tomography (FDG-PET) in patients with rheumatoid arthritis (RA) who are synthetic
      disease-modifying antirheumatic drugs (dMARD) inadequate responders and are naive to biologic
      therapy.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Adults aged 50-75

          -  Diagnosis of RA according to the revised 1987 American College of Rheumatology (ACR;
             formerly American Rheumatism Association), criteria.

          -  Patients who have had an inadequate response to non-biologic disease-modifying
             anti-rheumatic drug (DMARD) and are naïve to biologic agents.

          -  Presence of plaque inflammation, identified during secondary screening, defined as a
             target to baseline (TBR ratio) ≥ 1.7 in the carotid artery or ascending aorta.

          -  Not wheelchair or bedbound.

          -  At screening, active RA consisting of ≥4 swollen joints (28 joint count) and ≥ 4
             tender joints (28 joint count) and any one of the following criteria:

               -  Erythrocyte sedimentation rate (ESR) (Westergren) ≥ upper limit normal

               -  CRP ≥ upper limit normal

          -  If using other non-biologic DMARDS, (ex: methotrexate, sulfasalazine,
             hydroxychloroquine, azathioprine, cyclosporine, leflunomide), patient must demonstrate
             inadequate response, be on stable dose(s) for at least 4 weeks prior to baseline
             visit. For methotrexate: patients must be on methotrexate for at least 3 months with 4
             weeks stable dose, and will stay on stable dose during the study.

          -  taking corticosteroids, must be on stable doses of oral corticosteroids (≤ 10mg/day
             prednisone or equivalent) for at least 4 weeks prior to the baseline visit. Dose
             should remain stable throughout the study.

          -  Any investigational treatment not mentioned elsewhere must be discontinued for 4 weeks
             or 5 half lives, whichever is longer, prior to the baseline visit. Exposure to any
             investigational biologics should be discussed with the Sponsor.

          -  Signed informed consent (and informed assent of minor, if applicable).

          -  Men and women of reproductive potential must agree to use an acceptable method of
             birth control during treatment and for twelve months after completion of treatment.

          -  Subject has provided written informed consent

        Exclusion Criteria:

          -  Major surgery (including joint surgery) within 8 weeks prior to screening or planned
             major surgery within 6 months following randomization.

          -  Treatment with any investigational agent within 4 weeks (or 5 half-lives of the
             investigational drug, whichever is longer) of screening.

          -  Previous treatment with any cell-depleting therapies, including investigational agents
             or approved therapies, some examples include: CAMPATH, anti-CD4, anti-CD5, anti-CD3,
             anti-CD19 and anti-CD20.

          -  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 or other biologics (an exception to this criterion may be
             granted for single dose exposure upon application to the PI on a case-by-case basis).

          -  Any previous treatment with alkylating agents such as chlorambucil, or with total
             lymphoid irradiation.

          -  Currently taking a statin

          -  An intra-articular injection of steroids within 6 weeks of imaging

        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, Crohn's disease, or other symptomatic lower GI
             conditions that might predispose to perforations.)

          -  Diagnosis of liver disease or elevated hepatic enzymes, as defined by ALT, AST, or
             both > 1.5 x the upper limit of age-determined normal (ULN) or total bilirubin > ULN.

          -  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

          -  Any history of recent serious bacterial, viral, fungal, mycobacterial or other
             opportunistic infections.

          -  Have serologic evidence of current or past HIV, Hepatitis B, or Hepatitis C.

          -  Positive QuantiFERON TB test , history of tuberculosis, or active TB infection without
             at least 4 weeks of adequate therapy for TB.

          -  Active infection with EBV as defined by EBV viral load ≥ 10,000 copies per mL of whole
             blood.

          -  Active infection with CMV as defined by CMV viral load ≥ 10,000 copies per mL of whole
             blood.

          -  Any of the following hematologic abnormalities, confirmed by repeat tests:

          -  White blood count <3,000/μL or >14,000/μL;

          -  Lymphocyte count <500/μL;

          -  Platelet count <100,000 /μL;

          -  Hemoglobin <8.0 g/dL; or

          -  Neutrophil count <2,000 cells/μL.

          -  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.

          -  Primary or secondary immunodeficiency (history of or currently active) unless related
             to primary disease under investigation.

          -  Any medical or psychological condition that in the opinion of the principal
             investigator would interfere with safe completion of the trial.

          -  History of other malignancy within 5 years prior to screening, except for
             appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or
             Stage I uterine cancer.

          -  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.

          -  Rheumatic autoimmune disease other than RA, including SLE, MCTD, scleroderma,
             polymyositis, or significant systemic involvement secondary to RA (e.g., vasculitis,
             pulmonary fibrosis or Felty's Syndrome). Secondary Sjogrens syndrome with RA is
             allowable.

          -  Prior history of, or current inflammatory joint disease other than RA (e.g., gout,
             Lyme disease, seronegative spondyloarthropathy including reactive arthritis, psoriatic
             arthritis, arthropathy of inflammatory bowel disease).

          -  Relatively significant radiation exposure over the course of the year prior to
             randomization. Significant exposure is defined as:

             i) More than 2 PCI within 12 months of randomization ii) More than 2 myocardial
             perfusion studies within the past 12 months iii) More than 2 CT angiograms within the
             past 12 months iv) Any subjects with history of radiation therapy.

          -  Prior history of diverticulitis

          -  Contra-indications to MRI Imaging:

          -  Cardiac pacemaker that is not MRI compatible

          -  Surgical aneurysm clips

          -  Neurostimulator

          -  Implanted pumps

          -  Metal fragments in body / eyes

          -  Nitroglycerin patch that cannot be removed

          -  Colored contact lenses should not be worn in scanner

          -  Certain cochlear implants