Clinical trial NCT00105235: Immune System Suppression With Alemtuzumab and Tacrolimus in Liver Transplantation Patients
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Liver Disease
Liver Transplantation
Keywords: transplantation
liver transplant
rejection
tolerance
antibody induction
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Immune Tolerance Network (ITN)
First posted: 2005-03-11
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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 Regimens that are less toxic to or can eventually be withdrawn from transplant recipients are needed.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 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

Primary outcomes:
measure: Proportion of Participants Who Have Graft Loss or Death
timeFrame: Within 1 year of post-transplantation
Secondary outcomes:
measure: Proportion of Participants Who Had Graft Loss or Death
timeFrame: Within 2 years after initiation of immunosuppression withdrawal
measure: Number of Events: Immunosuppression-related Complications
timeFrame: From transplantation until study completion or participant termination (participants followed up to 60 months)
measure: Proportion of Participants Successfully Withdrawn From Immunosuppressants
timeFrame: From 1 year post- transplantation until study completion or participant termination (participants followed up to 48 months post-transplant)
measure: Proportion of Participants Successfully Withdrawn and Remain Off Immunosuppressants
timeFrame: From 1 year post- transplantation until study completion or participant termination (participants followed up to 48 months post-transplant)
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Denver
country: United States
facility: University of Colorado
state: Colorado
city: Miami
country: United States
facility: University of Miami School of Medicine
state: Florida
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Dallas
country: United States
facility: Baylor University
state: Texas
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
Study officials:
affiliation: University of Chicago
name: J. Richard Thistlethwaite, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: First MR. Tacrolimus based immunosuppression. J Nephrol. 2004 Nov-Dec;17 Suppl 8:S25-31.
citation: 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. doi: 10.1016/j.transproceed.2004.12.157.
citation: 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. doi: 10.1097/01.tp.0000116562.15920.43.