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

This study has been completed.
Sponsor:
Collaborator:
Immune Tolerance Network (ITN)
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00105235
First received: March 10, 2005
Last updated: November 23, 2012
Last verified: November 2012
  Purpose

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.


Condition Intervention Phase
Liver Disease
Liver Transplantation
Drug: Alemtuzumab
Drug: Cyclosporine
Drug: Mycophenolate mofetil
Drug: Tacrolimus
Procedure: Liver transplant
Procedure: Immunosuppression withdrawal
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Multicenter Trial to Assess the Safety and Efficacy of Campath-1H and Tacrolimus Followed By Immunosuppression Withdrawal in Liver Transplantation (ITN024ST)

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Proportion of Participants Who Have Graft Loss or Death [ Time Frame: Within 1 year of post-transplantation ] [ Designated as safety issue: Yes ]
    Proportion of participants who had liver graft loss or who died within 1 year of undergoing transplantation. Note: Participants who discontinued treatment or terminated the study prior to 1 year post transplantation are considered treatment failures and are included in this measure.


Secondary Outcome Measures:
  • Proportion of Participants Who Had 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 died or terminated from the study within 2 years of initiating immunosuppression withdrawal

  • Number of Events: Immunosuppression-related Complications [ Time Frame: From transplantation until study completion or participant termination (participants followed up to 60 months) ] [ Designated as safety issue: Yes ]
    Certain events are associated with immunosuppression. This measure looks at post-transplant infection, post-transplant malignancies, post-transplant diabetes, and post-transplant renal failure. Immunosuppression withdrawal is intended to reduce these type of events. However, reduction in immunosuppression can lead to complications in liver and renal function, as measured by acute rejection, chronic rejection, and post-transplant renal failure. Lower numbers for any of these events indicates greater success with transplantation and immunosuppression withdrawal (where applicable)

  • Proportion of Participants Successfully Withdrawn From Immunosuppressants [ Time Frame: From 1 year post- transplantation until study completion or participant termination (participants followed up to 48 months post-transplant) ] [ Designated as safety issue: Yes ]
    This measure of tolerance induction includes the proportion of participants who qualify for immunosuppression withdrawal as determined by a review of individual clinical results by a protocol withdrawal committee. Successful withdrawal definition: participants who remain off immunosuppression for at least 8 weeks.

  • Proportion of Participants Successfully Withdrawn and Remain Off Immunosuppressants [ Time Frame: From 1 year post- transplantation until study completion or participant termination (participants followed up to 48 months post-transplant) ] [ Designated as safety issue: No ]
    This measure of tolerance induction includes the proportion of participants who qualify for immunosuppression withdrawal as determined by a review of individual clinical results by a protocol withdrawal committee, were successfully withdrawn from immunosuppressants, and remained off immunosuppressants at the time the trial ended. Successful withdrawal definition: participants who remain off immunosuppression for at least 8 weeks and do not restart immunosuppressant drugs after successful withdrawal.


Enrollment: 27
Study Start Date: June 2005
Study Completion Date: March 2011
Primary Completion Date: March 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Alemtuzumab
Liver transplant, with two in-patient infused doses of alemtuzumab; followed by maintenance immunotherapy with cyclosporine, mycophenolate mofetil, and/or tacrolimus; with possible immunosuppression withdrawal
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

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00105235

Locations
United States, California
University of California, San Francisco
San Francisco, California, United States, 94143
United States, Colorado
University of Colorado
Denver, Colorado, United States, 80262
United States, Florida
University of Miami School of Medicine
Miami, Florida, United States, 33101
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
United States, Ohio
Cleveland Clinic
Cleveland, Ohio, United States, 44195
United States, Pennsylvania
University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
United States, Texas
Baylor University
Dallas, Texas, United States, 75246
United States, Wisconsin
University of Wisconsin
Madison, Wisconsin, United States, 53792
Canada, Alberta
University of Alberta
Edmonton, Alberta, Canada
Sponsors and Collaborators
Immune Tolerance Network (ITN)
Investigators
Principal Investigator: J. Richard Thistlethwaite, MD University of Chicago
  More Information

Additional Information:
Publications:
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00105235     History of Changes
Other Study ID Numbers: DAIT ITN024ST
Study First Received: March 10, 2005
Results First Received: March 2, 2012
Last Updated: November 23, 2012
Health Authority: United States: Federal Government
United States: Institutional Review Board

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
transplantation
liver transplant
rejection
tolerance
antibody induction

Additional relevant MeSH terms:
Liver Diseases
Digestive System Diseases
Cyclosporins
Cyclosporine
Mycophenolate mofetil
Mycophenolic Acid
Tacrolimus
Alemtuzumab
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Dermatologic Agents
Antirheumatic Agents
Antibiotics, Antineoplastic
Antineoplastic Agents

ClinicalTrials.gov processed this record on August 28, 2014