Immune System Suppression With Alemtuzumab and Tacrolimus in Liver Transplantation Patients (TILT)

• Proportion of Participants Who Have Graft Loss or Death [ Time Frame: Within 2 years after initiation of immunosuppression withdrawal ] [ Designated as safety issue: Yes ]
  Proportion of participants who had liver graft loss or who dies within 2 years of initiating immunosuppression withdrawal
• From Transplantation Until Study Completion or Participant Termination (Participants Followed up to 60 Months) [ Time Frame: Throughout study participation ] [ Designated as safety issue: Yes ]
• Measures of Tolerance Induction [ Time Frame: At 1 year post-transplant until study completion or participant termination (participants followed up to 48 months post-transplant) ] [ Designated as safety issue: Yes ]

• Proportion of participants who have graft loss or who die within 2 years after initiation of immunosuppression withdrawal
• incidence of immunosuppression-related complications
• measures of tolerance induction

Alemtuzumab is a man-made antibody used to treat certain blood disorders. Tacrolimus is a drug used to decrease immune system activity in people who have received organ transplants so that the new organ will not be rejected. This study will determine whether treatment with alemtuzumab and tacrolimus is effective in preventing organ rejection and maintaining the recipient's health after liver transplantation in patients with end-stage liver disease, and whether gradual tapering of tacrolimus treatment is safe for these patients.

Organ transplantation is a common procedure in hospitals, but organ rejection and serious side effects are potential problems for the patient. Alemtuzumab is a monoclonal antibody that binds to and depletes excess T cells in the bone marrow of leukemia patients. In this study, alemtuzumab will destroy the recipient's white blood cells (WBCs) at the time of transplantation. It is hoped that WBCs produced after alemtuzumab administration will recognize the transplanted liver as "self" and not reject the new liver.

Drugs that suppress the immune system, such as tacrolimus, have contributed to increased success of transplantation. However, to prevent organ rejection, transplant recipients need to take immunosuppressive drugs for the rest of their lives, and these drugs make patients more susceptible to infection, endangering their health and survival. Regimens that are less toxic to or can eventually be withdrawn from transplant recipients are needed. This study will evaluate the effects of two in-patient doses of alemtuzumab followed by maintenance antirejection medication given to liver transplant patients post-transplant. This study will also determine if post-transplant tacrolimus therapy can be slowly and safely tapered off and withdrawn a year after transplant. Participants in this study will be patients with end-stage liver disease who will undergo liver transplantation at the start of the study.

This study will last at least 2 years. Patients will undergo liver transplantation at the start of the study on Day 0. Patients will receive in-patient infusions of alemtuzumab on Days 0 and 4. Starting on Day 1, patients will receive oral cyclosporine, mycophenolate mofetil, and/or tacrolimus daily. Patients will be hospitalized for at least 1 week after transplantation. Because of suppression of patients' immune systems by alemtuzumab and these other immunosuppressants, they will also receive prophylactic medications for a minimum of 3 months after transplantation to prevent opportunistic infections.

There will be at least eight study visits; they will occur at Days 4, 7, and 14 and at Months 1, 3, 6, 9, and 12. Patients will have liver biopsies at Day 0 and Months 6 and 12. At Month 12, participants will have assessments and blood tests to determine if they meet certain criteria and are eligible to undergo tacrolimus tapering. Patients eligible for tapering will undergo a 12-month gradual withdrawal of tacrolimus; they will be followed for an additional 2 years, with study visits at Months 18, 24, 30, and 36. Patients ineligible for tacrolimus tapering will continue taking their antirejection medication for the duration of the study; they will be followed for an additional year, with study visits at Months 18 and 24.

• Liver Disease
• Liver Transplantation

• Drug: Alemtuzumab
  T-cell depleting monoclonal antibody; two doses by intravenous infusion on Days 0 and 4
  Other Name: Campath
• Drug: Cyclosporine
  Oral immunosuppressant
• Drug: Mycophenolate mofetil
  Oral immunosuppressant
  Other Name: CellCept
• Drug: Tacrolimus
  Oral immunosuppressant
  Other Names:

  • FK-506
  • Fujimycin
• Procedure: Liver transplant
  Occurs at study entry
• Procedure: Immunosuppression withdrawal
  Beginning no earlier than Year 1

• First MR. Tacrolimus based immunosuppression. J Nephrol. 2004 Nov-Dec;17 Suppl 8:S25-31. Review.
• Tryphonopoulos P, Madariaga JR, Kato T, Nishida S, Levi DM, Moon J, Selvaggi G, De Faria W, Regev A, Bejarano P, Khaled A, Safdar K, Esquenazi V, Weppler D, Yoshida H, Ruiz P, Miller J, Tzakis AG. The impact of Campath 1H induction in adult liver allotransplantation. Transplant Proc. 2005 Mar;37(2):1203-4.
• Tzakis AG, Tryphonopoulos P, Kato T, Nishida S, Levi DM, Madariaga JR, Gaynor JJ, De Faria W, Regev A, Esquenazi V, Weppler D, Ruiz P, Miller J. Preliminary experience with alemtuzumab (Campath-1H) and low-dose tacrolimus immunosuppression in adult liver transplantation. Transplantation. 2004 Apr 27;77(8):1209-14. Erratum in: Transplantation. 2004 Aug 15;78(3):489.

Inclusion Criteria:

• Diagnosis of nonimmune, nonviral, end-stage liver disease
• Need liver transplant
• Willing to use acceptable means of contraception for the duration of the study

Exclusion Criteria:

• Previous transplant
• Multiorgan transplant or living donor transplant
• Donor liver from a donor positive for antibody against hepatitis B core antigen or hepatitis C virus
• Donor liver from a non-heart-beating donor
• Liver failure due to autoimmune disease, such as autoimmune hepatitis, primary sclerosing cholangitis, or primary biliary cirrhosis
• Hepatitis B or C virus infection
• HIV infection
• Stage III or higher hepatocellular cancer based on pre-transplant imaging
• History of cancer. Patients with hepatocellular cancer, adequately treated in situ cervical carcinoma, or adequately treated basal or squamous cell carcinoma of skin are not excluded.
• Active systemic infection at the time of transplantation
• Clinically significant chronic renal, cardiovascular, or cerebrovascular disease
• Any investigational drug within 6 weeks of study entry
• Hypersensitivity to alemtuzumab or tacrolimus