Tocilizumab for Renal Graft Inflammation

This is a prospective randomized controlled study of kidney transplant recipients with SCI on 6-month surveillance kidney biopsies. SCI for the purpose of this study is defined as 10-50% total parenchymal mononuclear inflammation (Banff ti1-ti2) with <i2,t2 concurrent lesions.

After enrollment, study participants subjects will be randomized to group 1 (standard of care group) or group 2 (tocilizumab (TCZ) group). Block randomization will be performed by the UCSF investigational pharmacy using computer-generated random numbers. The pathologist will be blinded to the randomization.

Group 1 (standard of care group) will continue their usual immunosuppression and not receive any specific intervention.

Group 2 (TCZ group) will receive tocilizumab 8 mg/kg intravenously at four-week intervals for a total of 6 doses.In addition, they will continue their usual immunosuppressive regimen.

As noted above, both groups will continue their usual maintenance immunosuppression regimen. Therefore, recipients who are already receiving prednisone will continue it at 5 mg/day. Recipients on prednisone-free regimens will remain prednisone-free. Mycophenolate mofetil will be continued at the same dose as at the time of the biopsy. Tacrolimus dosing will be adjusted to aim for trough levels of 5-8 mcg/L.

The study period will be 12 months (6 months of therapy plus 6 months of extended follow up- see Study Schema). Any episodes of infections, renal allograft dysfunctions, rejections or other clinical events during the study period will be treated per the usual standard of care.

All participants will be seen by the study PI or co-investigator at monthly study visits. A focused history and physical exam will be performed, including queries for drug toxicities and signs/ symptom of infections. All participants will obtain laboratory tests at intervals of 4 weeks, consisting of a complete blood count, serum electrolytes, BUN and serum creatinine, fasting glucose, liver function tests and 12-hour trough tacrolimus levels. Lipid panels will be obtained at baseline, then every 12 weeks an at study termination.The outpatient electronic medical record will be queried twiceweekly by the study coordinator for any new laboratory results on study participants. Laboratory data on all study participants will be reviewed weekly by the study PI.

The 12-month surveillance biopsy will be performed at the end of therapy (6 months after study enrollment).

Inclusion criteria

• All kidney transplant recipients with SCI on 6-month surveillance biopsy.
• Maintenance immunosuppression regimens containing tacrolimus and MMF with or without prednisone.
• Ability to provide written informed consent for the study.
• 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.

Exclusion criteria

General:

• Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization.

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 screening.
• Previous treatment with any cell-depleting therapies, including investigational agents or approved therapies, some examples are CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19 and anti-CD20, except Thymoglobulin.
• 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 (an exception to this criterion may be granted for single dose exposure upon application to the sponsor on a case-by-case basis).
• Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation.

Exclusions for General Safety:

• Presence of acute cellular (Banff Type 1-3) or antibody-mediated rejection on 6-month surveillance biopsy or on biopsies for-cause in the previous 6 months.
• History of positive urine or serum screening for BK virus (defined as a quantitative BK virus PCR in urine > 0.5 million copies/ml or any detectable BK viremia) within the first 6 months post-transplant.
• 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 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 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. Patients treated for tuberculosis with no recurrence in 3 years are permitted. (Appendix 8).
• 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 10 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 20 years unless related to primary disease under investigation.
• 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.
• Patients with lack of peripheral venous access.

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 ml/min/1.73 m2.
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 1.5 times upper limit of normal (ULN)
• Total Bilirubin > 1.5 times 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