| Purpose: |
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In this Phase I/II trial, 10 highly sensitized patients will be entered after informed
consent and will receive Intravenous Immunoglobulin (IVIG) at 2 gm/kg + Tocilizumab 8 mg/kg
x 5 doses on days 15, 45, 75, 105 and 135. If robust reductions in anti-HLA antibody are
seen, patients will progress to kidney transplantation when an "acceptable" crossmatch is
achieved with a living donor (LD) or deceased donor (DD). Those receiving transplants will
also receive Tocilizumab infusion monthly X7 doses post-transplant. All subjects will have
intensive monitoring of Donor Specific Antibodies (DSA), viral PCRs and routine
post-transplant labs. At 6 months post-transplant, those who have retained their
transplanted kidney will have a protocol biopsy.
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| Criteria: |
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Inclusion Criteria:
- End-stage renal disease.
- No known contraindications for therapy with IGIV10%/Actemra®.
- Age 18-65 years at the time of screening.
- CPRA > 50% demonstrated on 3 consecutive samples, UNOS wait time sufficient to
allow DD offers, history of sensitizing events, positive crossmatch with the intended
donor. LDs with DSA and Crossmatch positivity.
- Subject/Parent/Guardian must be able to understand and provide 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 are CAMPATH, anti-CD4, anti-CD5,
anti¬CD3, anti-CD19 and anti-CD20 within 6 months of baseline.
- Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column within 6
months of baseline
- Immunization with a live/attenuated vaccine within 2 months 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, (within 1 year)
or with total lymphoid irradiation.
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), 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). These are limited to non-access related infections.
- 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.
- 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.
- 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):
- 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
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