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

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00105235
• Collaborator: Immune Tolerance Network (ITN) (Other)
• Enrollment: 27
• Locations: 9
• Arm: 1
• Duration (Months): 69
• Patients Per Site: 3
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

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

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 Regimens that are less toxic to or can eventually be withdrawn from transplant recipients are needed.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

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (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)
• Study Start Date: Jun 1, 2005
• Actual Primary Completion Date: Mar 1, 2007
• Actual Study Completion Date: Mar 1, 2011

Arms and Interventions

Arm

Intervention/Treatment

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 Names: Campath ; Drug: Cyclosporine; Oral immunosuppressant; Drug: Mycophenolate mofetil; Oral immunosuppressant; Other Names: 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

Outcome Measures

Primary Outcome Measures

1. Proportion of Participants Who Have Graft Loss or Death [Within 1 year of post-transplantation]

   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

1. Proportion of Participants Who Had Graft Loss or Death [Within 2 years after initiation of immunosuppression withdrawal]

   Proportion of participants who had liver graft loss or who died or terminated from the study within 2 years of initiating immunosuppression withdrawal

2. Number of Events: Immunosuppression-related Complications [From transplantation until study completion or participant termination (participants followed up to 60 months)]

   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)

3. Proportion of Participants Successfully Withdrawn From Immunosuppressants [From 1 year post- transplantation until study completion or participant termination (participants followed up to 48 months post-transplant)]

   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.

4. Proportion of Participants Successfully Withdrawn and Remain Off Immunosuppressants [From 1 year post- transplantation until study completion or participant termination (participants followed up to 48 months post-transplant)]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Francisco	San Francisco	California	United States	94143
2	University of Colorado	Denver	Colorado	United States	80262
3	University of Miami School of Medicine	Miami	Florida	United States	33101
4	University of Michigan	Ann Arbor	Michigan	United States	48109
5	Cleveland Clinic	Cleveland	Ohio	United States	44195
6	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
7	Baylor University	Dallas	Texas	United States	75246
8	University of Wisconsin	Madison	Wisconsin	United States	53792
9	University of Alberta	Edmonton	Alberta	Canada

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)
• Immune Tolerance Network (ITN)

Investigators

• Principal Investigator: J. Richard Thistlethwaite, MD, University of Chicago

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here for the Immune Tolerance Network Web site

Publications

• 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.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT00105235
• Other Study ID Numbers: DAIT ITN024ST
• First Posted: Mar 11, 2005
• Last Update Posted: Dec 27, 2012
• Last Verified: Nov 1, 2012

• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): transplantation; liver transplant; rejection; tolerance; antibody induction
• Additional relevant MeSH terms: Liver Diseases; Cyclosporine; Mycophenolic Acid; Alemtuzumab; Tacrolimus; Cyclosporins

Study Results

Participant Flow

Recruitment Details	Recruitment details: Eight centers in the United States and one center in Canada enrolled 27 participants with end-stage liver disease who met entry criteria between February 2005 and May 2006.

Arm/Group Title	Alemtuzumab
Arm/Group Description	Recipients of a liver allograft for end-stage liver disease received a 30 mg IV dose of alemtuzumab on study days 0 and 4 (immunosuppressive induction). Beginning on study day 1, participants received tacrolimus orally (dose adjusted to yield trough blood levels of 5-12 ng/mL) with or without mycophenolate orally (<= 1.5g twice daily), at the discretion of the investigator. Six months post transplant, the tacrolimus dose was adjusted to yield trough blood levels of 5-10 ng/mL. Participants with significant toxicities related to tacrolimus were changed to cyclosporine (CsA), with the dose adjusted to maintain trough blood levels of 200-350 ng/mL during the first 3 months post transplant and 100-300 ng/mL from month 4 until CsA tapering was initiated. Maintenance immunosuppression was maintained for at least 12 months. At 12 months, participants were assessed for immune reconstitution and for the ability to undergo tapering and subsequent withdrawal of immunosuppression
Period Title: Overall Study
STARTED	27
COMPLETED	20
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	Alemtuzumab
Arm/Group Description	Recipients of a liver allograft for end-stage liver disease received a 30 mg IV dose of alemtuzumab on study days 0 and 4 (immunosuppressive induction). Beginning on study day 1, participants received tacrolimus orally (dose adjusted to yield trough blood levels of 5-12 ng/mL) with or without mycophenolate orally (<= 1.5g twice daily), at the discretion of the investigator. Six months post transplant, the tacrolimus dose was adjusted to yield trough blood levels of 5-10 ng/mL. Participants with significant toxicities related to tacrolimus were changed to cyclosporine (CsA), with the dose adjusted to maintain trough blood levels of 200-350 ng/mL during the first 3 months post transplant and 100-300 ng/mL from month 4 until CsA tapering was initiated. Maintenance immunosuppression was maintained for at least 12 months. At 12 months, participants were assessed for immune reconstitution and for the ability to undergo tapering and subsequent withdrawal of immunosuppression
Overall Participants	27
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	25 92.6%
>=65 years	2 7.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.5 (10.3)
Sex: Female, Male (Count of Participants)
Female	8 29.6%
Male	19 70.4%
Region of Enrollment (participants) [Number]
United States	26 96.3%
Canada	1 3.7%

Outcome Measures

1. Primary Outcome

Title	Proportion of Participants Who Have Graft Loss or Death
Description	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.
Time Frame	Within 1 year of post-transplantation

Outcome Measure Data

Analysis Population Description

Safety Sample

Arm/Group Title	Alemtuzumab
Arm/Group Description	Recipients of a liver allograft for end-stage liver disease received a 30 mg IV dose of alemtuzumab on study days 0 and 4 (immunosuppressive induction). Beginning on study day 1, participants received tacrolimus orally (dose adjusted to yield trough blood levels of 5-12 ng/mL) with or without mycophenolate orally (<= 1.5g twice daily), at the discretion of the investigator. Six months post transplant, the tacrolimus dose was adjusted to yield trough blood levels of 5-10 ng/mL. Participants with significant toxicities related to tacrolimus were changed to cyclosporine (CsA), with the dose adjusted to maintain trough blood levels of 200-350 ng/mL during the first 3 months post transplant and 100-300 ng/mL from month 4 until CsA tapering was initiated. Maintenance immunosuppression was maintained for at least 12 months. At 12 months, participants were assessed for immune reconstitution and for the ability to undergo tapering and subsequent withdrawal of immunosuppression
Measure Participants	27
Number [Proportion of Participants]	0.22 0.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alemtuzumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Proportion
	Estimated Value	0.22
	Confidence Interval	(2-Sided) 95%; .086 to .423
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Proportion of Participants Who Had Graft Loss or Death
Description	Proportion of participants who had liver graft loss or who died or terminated from the study within 2 years of initiating immunosuppression withdrawal
Time Frame	Within 2 years after initiation of immunosuppression withdrawal

Outcome Measure Data

Analysis Population Description

Participants who initiated immunosuppression withdrawal

Arm/Group Title	Alemtuzumab
Arm/Group Description	Recipients of a liver allograft for end-stage liver disease received a 30 mg IV dose of alemtuzumab on study days 0 and 4 (immunosuppressive induction). Beginning on study day 1, participants received tacrolimus orally (dose adjusted to yield trough blood levels of 5-12 ng/mL) with or without mycophenolate orally (<= 1.5g twice daily), at the discretion of the investigator. Six months post transplant, the tacrolimus dose was adjusted to yield trough blood levels of 5-10 ng/mL. Participants with significant toxicities related to tacrolimus were changed to cyclosporine (CsA), with the dose adjusted to maintain trough blood levels of 200-350 ng/mL during the first 3 months post transplant and 100-300 ng/mL from month 4 until CsA tapering was initiated. Maintenance immunosuppression was maintained for at least 12 months. At 12 months, participants were assessed for immune reconstitution and for the ability to undergo tapering and subsequent withdrawal of immunosuppression
Measure Participants	10
Number [Proportion of Participants]	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alemtuzumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Proportion
	Estimated Value	0
	Confidence Interval	(2-Sided) 95%; 0 to 0.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number of Events: Immunosuppression-related Complications
Description	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)
Time Frame	From transplantation until study completion or participant termination (participants followed up to 60 months)

Outcome Measure Data

Analysis Population Description

Safety Sample

Arm/Group Title	Withdrawal Never Started	Completed Withdrawal and Remains Off Immunosuppression	Completed Withdrawal and Restarted Immunosuppression	Discontinued Immunosuppression Withdrawal
Arm/Group Description	Recipients of a liver allograft for end-stage liver disease received a 30 mg IV dose of alemtuzumab on study days 0 and 4 (immunosuppressive induction). Beginning on study day 1, participants received tacrolimus orally (dose adjusted to yield trough blood levels of 5-12 ng/mL) with or without mycophenolate orally (<= 1.5g twice daily), at the discretion of the investigator. Six months post transplant, the tacrolimus dose was adjusted to yield trough blood levels of 5-10 ng/mL. Participants with significant toxicities related to tacrolimus were changed to cyclosporine (CsA), with the dose adjusted to maintain trough blood levels of 200-350 ng/mL during the first 3 months post transplant and 100-300 ng/mL from month 4 until CsA tapering was initiated. Maintenance immunosuppression was maintained for at least 12 months. At 12 months, participants were assessed for immune reconstitution and for the ability to undergo tapering and subsequent withdrawal of immunosuppression	Recipients of a liver allograft for end-stage liver disease received a 30 mg IV dose of alemtuzumab on study days 0 and 4 (immunosuppressive induction). Beginning on study day 1, participants received tacrolimus orally (dose adjusted to yield trough blood levels of 5-12 ng/mL) with or without mycophenolate orally (<= 1.5g twice daily), at the discretion of the investigator. Six months post transplant, the tacrolimus dose was adjusted to yield trough blood levels of 5-10 ng/mL. Participants with significant toxicities related to tacrolimus were changed to cyclosporine (CsA), with the dose adjusted to maintain trough blood levels of 200-350 ng/mL during the first 3 months post transplant and 100-300 ng/mL from month 4 until CsA tapering was initiated. Maintenance immunosuppression was maintained for at least 12 months. At 12 months, participants were assessed for immune reconstitution and for the ability to undergo tapering and subsequent withdrawal of immunosuppression	Recipients of a liver allograft for end-stage liver disease received a 30 mg IV dose of alemtuzumab on study days 0 and 4 (immunosuppressive induction). Beginning on study day 1, participants received tacrolimus orally (dose adjusted to yield trough blood levels of 5-12 ng/mL) with or without mycophenolate orally (<= 1.5g twice daily), at the discretion of the investigator. Six months post transplant, the tacrolimus dose was adjusted to yield trough blood levels of 5-10 ng/mL. Participants with significant toxicities related to tacrolimus were changed to cyclosporine (CsA), with the dose adjusted to maintain trough blood levels of 200-350 ng/mL during the first 3 months post transplant and 100-300 ng/mL from month 4 until CsA tapering was initiated. Maintenance immunosuppression was maintained for at least 12 months. At 12 months, participants were assessed for immune reconstitution and for the ability to undergo tapering and subsequent withdrawal of immunosuppression	Recipients of a liver allograft for end-stage liver disease received a 30 mg IV dose of alemtuzumab on study days 0 and 4 (immunosuppressive induction). Beginning on study day 1, participants received tacrolimus orally (dose adjusted to yield trough blood levels of 5-12 ng/mL) with or without mycophenolate orally (<= 1.5g twice daily), at the discretion of the investigator. Six months post transplant, the tacrolimus dose was adjusted to yield trough blood levels of 5-10 ng/mL. Participants with significant toxicities related to tacrolimus were changed to cyclosporine (CsA), with the dose adjusted to maintain trough blood levels of 200-350 ng/mL during the first 3 months post transplant and 100-300 ng/mL from month 4 until CsA tapering was initiated. Maintenance immunosuppression was maintained for at least 12 months. At 12 months, participants were assessed for immune reconstitution and for the ability to undergo tapering and subsequent withdrawal of immunosuppression
Measure Participants	17	2	2	6
Acute Rejection	6	0	0	0
Chronic Rejection	1	0	0	0
Post-transplant Infection	76	2	10	11
Post-transplant Malignancies	1	0	0	0
Post-transplant Diabetes	0	0	0	1
Post-transplant Renal Failure	11	0	2	1

4. Secondary Outcome

Title	Proportion of Participants Successfully Withdrawn From Immunosuppressants
Description	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.
Time Frame	From 1 year post- transplantation until study completion or participant termination (participants followed up to 48 months post-transplant)

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Alemtuzumab
Arm/Group Description	Recipients of a liver allograft for end-stage liver disease received a 30 mg IV dose of alemtuzumab on study days 0 and 4 (immunosuppressive induction). Beginning on study day 1, participants received tacrolimus orally (dose adjusted to yield trough blood levels of 5-12 ng/mL) with or without mycophenolate orally (<= 1.5g twice daily), at the discretion of the investigator. Six months post transplant, the tacrolimus dose was adjusted to yield trough blood levels of 5-10 ng/mL. Participants with significant toxicities related to tacrolimus were changed to cyclosporine (CsA), with the dose adjusted to maintain trough blood levels of 200-350 ng/mL during the first 3 months post transplant and 100-300 ng/mL from month 4 until CsA tapering was initiated. Maintenance immunosuppression was maintained for at least 12 months. At 12 months, participants were assessed for immune reconstitution and for the ability to undergo tapering and subsequent withdrawal of immunosuppression
Measure Participants	27
Number [Proportion of Participants]	0.2 0.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alemtuzumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Proportion
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95%; 0.04 to 0.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Proportion of Participants Successfully Withdrawn and Remain Off Immunosuppressants
Description	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.
Time Frame	From 1 year post- transplantation until study completion or participant termination (participants followed up to 48 months post-transplant)

Outcome Measure Data

Analysis Population Description

Intent-to-treat

Arm/Group Title	Alemtuzumab
Arm/Group Description	Recipients of a liver allograft for end-stage liver disease received a 30 mg IV dose of alemtuzumab on study days 0 and 4 (immunosuppressive induction). Beginning on study day 1, participants received tacrolimus orally (dose adjusted to yield trough blood levels of 5-12 ng/mL) with or without mycophenolate orally (<= 1.5g twice daily), at the discretion of the investigator. Six months post transplant, the tacrolimus dose was adjusted to yield trough blood levels of 5-10 ng/mL. Participants with significant toxicities related to tacrolimus were changed to cyclosporine (CsA), with the dose adjusted to maintain trough blood levels of 200-350 ng/mL during the first 3 months post transplant and 100-300 ng/mL from month 4 until CsA tapering was initiated. Maintenance immunosuppression was maintained for at least 12 months. At 12 months, participants were assessed for immune reconstitution and for the ability to undergo tapering and subsequent withdrawal of immunosuppression
Measure Participants	27
Number [Proportion of Participants]	0.1 0.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alemtuzumab
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Proportion
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; 0.01 to 0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	From transplantation until study completion or participant termination (participants followed up to 48 months post-transplantation)
Adverse Event Reporting Description	This study graded the severity of adverse events experienced by the study participant according to criteria set forth in the National Cancer Institute's Common Terminology Criteria for Adverse Events Version 3.0 (June 10, 2003)
Arm/Group Title	Alemtuzumab
Arm/Group Description	Recipients of a liver allograft for end-stage liver disease received a 30 mg IV dose of alemtuzumab on study days 0 and 4 (immunosuppressive induction). Beginning on study day 1, participants received tacrolimus orally (dose adjusted to yield trough blood levels of 5-12 ng/mL) with or without mycophenolate orally (<= 1.5g twice daily), at the discretion of the investigator. Six months post transplant, the tacrolimus dose was adjusted to yield trough blood levels of 5-10 ng/mL. Participants with significant toxicities related to tacrolimus were changed to cyclosporine (CsA), with the dose adjusted to maintain trough blood levels of 200-350 ng/mL during the first 3 months post transplant and 100-300 ng/mL from month 4 until CsA tapering was initiated. Maintenance immunosuppression was maintained for at least 12 months. At 12 months, participants were assessed for immune reconstitution and for the ability to undergo tapering and subsequent withdrawal of immunosuppression
All Cause Mortality
	Alemtuzumab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Alemtuzumab
	Affected / at Risk (%)	# Events
Total	27/27 (100%)
Blood and lymphatic system disorders
Anaemia	3/27 (11.1%)	3
Coagulopathy	1/27 (3.7%)	1
Neutropenia	1/27 (3.7%)	1
Pancytopenia	1/27 (3.7%)	1
Thrombocytopenia	2/27 (7.4%)	2
Cardiac disorders
Bradycardia	1/27 (3.7%)	1
Cardio-respiratory arrest	1/27 (3.7%)	1
Tachycardia	1/27 (3.7%)	1
Ventricular tachycardia	1/27 (3.7%)	1
Gastrointestinal disorders
Abdominal discomfort	1/27 (3.7%)	1
Ascites	1/27 (3.7%)	2
Gastric ileus	1/27 (3.7%)	1
Gastrointestinal haemorrhage	2/27 (7.4%)	2
Oesophageal varices haemorrhage	1/27 (3.7%)	1
Peritoneal haemorrhage	1/27 (3.7%)	1
Umbilical hernia	1/27 (3.7%)	1
Varices oesophageal	1/27 (3.7%)	1
General disorders
Chest pain	1/27 (3.7%)	1
Multi-organ failure	1/27 (3.7%)	1
Pyrexia	2/27 (7.4%)	4
Hepatobiliary disorders
Bile duct stenosis	6/27 (22.2%)	8
Cholestasis	1/27 (3.7%)	1
Hepatic artery thrombosis	1/27 (3.7%)	1
Hepatic cirrhosis	1/27 (3.7%)	1
Hepatic failure	1/27 (3.7%)	1
Hepatic steatosis	2/27 (7.4%)	2
Liver disorder	1/27 (3.7%)	1
Immune system disorders
Hypersensitivity	1/27 (3.7%)	1
Transplant rejection	9/27 (33.3%)	12
Infections and infestations
Abdominal infection	1/27 (3.7%)	1
Bacteraemia	2/27 (7.4%)	3
Clostridium difficile colitis	1/27 (3.7%)	1
Endocarditis	1/27 (3.7%)	1
Gastroenteritis viral	1/27 (3.7%)	1
Hydrocele male infected	1/27 (3.7%)	1
Influenza	1/27 (3.7%)	1
Liver abscess	1/27 (3.7%)	1
Lung infection pseudomonal	2/27 (7.4%)	2
Osteomyelitis	1/27 (3.7%)	1
Peritonitis bacterial	3/27 (11.1%)	3
Pneumonia	2/27 (7.4%)	2
Sepsis	3/27 (11.1%)	4
Urinary tract infection	2/27 (7.4%)	2
Urinary tract infection enterococcal	1/27 (3.7%)	1
Wound infection	1/27 (3.7%)	1
Injury, poisoning and procedural complications
Collapse of lung	1/27 (3.7%)	1
Femoral neck fracture	1/27 (3.7%)	1
Graft loss	1/27 (3.7%)	1
Hip fracture	2/27 (7.4%)	2
Post procedural haemorrhage	2/27 (7.4%)	2
Road traffic accident	1/27 (3.7%)	1
Venous injury	1/27 (3.7%)	1
Weaning failure	1/27 (3.7%)	1
Investigations
Liver function test abnormal	3/27 (11.1%)	3
Metabolism and nutrition disorders
Dehydration	2/27 (7.4%)	3
Hyperkalaemia	2/27 (7.4%)	3
Hypoglycaemia	1/27 (3.7%)	1
Metabolic acidosis	2/27 (7.4%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
B-cell lymphoma	1/27 (3.7%)	1
Benign small intestinal neoplasm	1/27 (3.7%)	1
Hepatic neoplasm malignant	1/27 (3.7%)	1
Squamous cell carcinoma	1/27 (3.7%)	1
Nervous system disorders
Central pontine myelinolysis	1/27 (3.7%)	1
Psychiatric disorders
Mental status changes	2/27 (7.4%)	2
Paranoia	1/27 (3.7%)	1
Renal and urinary disorders
Renal failure	1/27 (3.7%)	1
Renal failure acute	3/27 (11.1%)	3
Renal tubular necrosis	1/27 (3.7%)	1
Reproductive system and breast disorders
Menorrhagia	1/27 (3.7%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	4/27 (14.8%)	4
Hypercapnia	1/27 (3.7%)	1
Pleural effusion	2/27 (7.4%)	2
Pulmonary embolism	1/27 (3.7%)	1
Respiratory arrest	1/27 (3.7%)	1
Respiratory distress	1/27 (3.7%)	1
Respiratory failure	3/27 (11.1%)	3
Vascular disorders
Deep vein thrombosis	2/27 (7.4%)	2
Other (Not Including Serious) Adverse Events
	Alemtuzumab
	Affected / at Risk (%)	# Events
Total	26/27 (96.3%)
Blood and lymphatic system disorders
Anaemia	18/27 (66.7%)	36
Coagulopathy	3/27 (11.1%)	4
Leukopenia	10/27 (37%)	16
Lymphopenia	2/27 (7.4%)	2
Neutropenia	7/27 (25.9%)	9
Splenomegaly	2/27 (7.4%)	2
Thrombocytopenia	9/27 (33.3%)	16
Cardiac disorders
Atrial fibrillation	2/27 (7.4%)	3
Bradycardia	2/27 (7.4%)	2
Palpitations	2/27 (7.4%)	2
Pericardial effusion	2/27 (7.4%)	3
Tachycardia	4/27 (14.8%)	4
Ear and labyrinth disorders
Ear pain	2/27 (7.4%)	2
Endocrine disorders
Hypothyroidism	4/27 (14.8%)	4
Eye disorders
Ocular icterus	2/27 (7.4%)	2
Gastrointestinal disorders
Abdominal discomfort	3/27 (11.1%)	3
Abdominal distension	9/27 (33.3%)	13
Abdominal pain	11/27 (40.7%)	16
Abdominal pain upper	3/27 (11.1%)	3
Ascites	5/27 (18.5%)	7
Constipation	17/27 (63%)	30
Diarrhoea	15/27 (55.6%)	23
Diverticulum	2/27 (7.4%)	2
Dyspepsia	5/27 (18.5%)	6
Dysphagia	3/27 (11.1%)	3
Flatulence	2/27 (7.4%)	2
Ileus	2/27 (7.4%)	2
Nausea	16/27 (59.3%)	24
Umbilical hernia	2/27 (7.4%)	2
Vomiting	5/27 (18.5%)	7
General disorders
Asthenia	4/27 (14.8%)	4
Fatigue	4/27 (14.8%)	4
Generalised oedema	6/27 (22.2%)	7
Oedema	6/27 (22.2%)	8
Oedema peripheral	16/27 (59.3%)	24
Pain	11/27 (40.7%)	17
Pyrexia	13/27 (48.1%)	25
Hepatobiliary disorders
Cholangitis	2/27 (7.4%)	2
Cholestasis	6/27 (22.2%)	6
Hepatic steatosis	4/27 (14.8%)	4
Hyperbilirubinaemia	5/27 (18.5%)	5
Jaundice	9/27 (33.3%)	11
Infections and infestations
Bacteraemia	4/27 (14.8%)	6
Cellulitis	2/27 (7.4%)	3
Clostridium difficile colitis	3/27 (11.1%)	4
Cytomegalovirus infection	2/27 (7.4%)	2
Fungal skin infection	3/27 (11.1%)	3
Localised infection	2/27 (7.4%)	2
Peritoneal infection	2/27 (7.4%)	2
Pneumonia	3/27 (11.1%)	3
Sinusitis	2/27 (7.4%)	5
Urinary tract infection	5/27 (18.5%)	8
Wound infection	2/27 (7.4%)	3
Injury, poisoning and procedural complications
Endotracheal intubation complication	2/27 (7.4%)	2
Incision site pain	7/27 (25.9%)	8
Incisional hernia	3/27 (11.1%)	4
Operative haemorrhage	2/27 (7.4%)	2
Post procedural bile leak	3/27 (11.1%)	4
Post procedural haemorrhage	2/27 (7.4%)	2
Procedural complication	2/27 (7.4%)	2
Procedural hypotension	2/27 (7.4%)	3
Procedural pain	8/27 (29.6%)	9
Wound secretion	2/27 (7.4%)	2
Investigations
Blood alkaline phosphatase increased	3/27 (11.1%)	3
Blood creatinine increased	7/27 (25.9%)	15
Blood magnesium decreased	4/27 (14.8%)	7
Blood phosphorus decreased	2/27 (7.4%)	4
Breath sounds abnormal	4/27 (14.8%)	6
Cardiac murmur	5/27 (18.5%)	5
Coagulation time prolonged	2/27 (7.4%)	3
Electrocardiogram abnormal	2/27 (7.4%)	2
Haematocrit decreased	2/27 (7.4%)	2
Hepatic enzyme increased	2/27 (7.4%)	2
International normalised ratio increased	3/27 (11.1%)	3
Liver function test abnormal	8/27 (29.6%)	8
Platelet count decreased	3/27 (11.1%)	3
Metabolism and nutrition disorders
Acidosis	2/27 (7.4%)	2
Anorexia	4/27 (14.8%)	4
Cachexia	3/27 (11.1%)	3
Decreased appetite	5/27 (18.5%)	5
Dehydration	7/27 (25.9%)	7
Failure to thrive	2/27 (7.4%)	2
Fluid overload	6/27 (22.2%)	8
Hyperglycaemia	14/27 (51.9%)	19
Hyperkalaemia	14/27 (51.9%)	24
Hyperlipidaemia	2/27 (7.4%)	2
Hyperphosphataemia	3/27 (11.1%)	3
Hypoalbuminaemia	3/27 (11.1%)	3
Hypocalcaemia	8/27 (29.6%)	8
Hypoglycaemia	3/27 (11.1%)	4
Hypokalaemia	14/27 (51.9%)	21
Hypomagnesaemia	10/27 (37%)	19
Hyponatraemia	5/27 (18.5%)	5
Hypophosphataemia	2/27 (7.4%)	2
Hypovolaemia	3/27 (11.1%)	4
Metabolic acidosis	3/27 (11.1%)	4
Metabolic alkalosis	2/27 (7.4%)	3
Musculoskeletal and connective tissue disorders
Arthralgia	3/27 (11.1%)	3
Back pain	8/27 (29.6%)	10
Muscle atrophy	3/27 (11.1%)	3
Muscle spasms	4/27 (14.8%)	4
Musculoskeletal pain	2/27 (7.4%)	2
Nervous system disorders
Dizziness	2/27 (7.4%)	2
Dysarthria	2/27 (7.4%)	2
Headache	9/27 (33.3%)	13
Neurotoxicity	2/27 (7.4%)	2
Sciatica	2/27 (7.4%)	2
Tremor	7/27 (25.9%)	9
Psychiatric disorders
Agitation	6/27 (22.2%)	8
Anxiety	7/27 (25.9%)	7
Confusional state	5/27 (18.5%)	5
Depression	7/27 (25.9%)	8
Insomnia	15/27 (55.6%)	20
Mental status changes	2/27 (7.4%)	2
Renal and urinary disorders
Renal failure	7/27 (25.9%)	7
Renal failure acute	3/27 (11.1%)	3
Reproductive system and breast disorders
Scrotal oedema	2/27 (7.4%)	3
Respiratory, thoracic and mediastinal disorders
Atelectasis	6/27 (22.2%)	6
Cough	5/27 (18.5%)	8
Dysphonia	2/27 (7.4%)	2
Dyspnoea	5/27 (18.5%)	7
Nasal congestion	2/27 (7.4%)	2
Pleural effusion	6/27 (22.2%)	7
Pneumothorax	2/27 (7.4%)	2
Productive cough	4/27 (14.8%)	4
Pulmonary oedema	4/27 (14.8%)	5
Rales	3/27 (11.1%)	3
Tachypnoea	2/27 (7.4%)	2
Wheezing	8/27 (29.6%)	8
Skin and subcutaneous tissue disorders
Ecchymosis	2/27 (7.4%)	2
Night sweats	2/27 (7.4%)	2
Petechiae	2/27 (7.4%)	3
Pruritus	10/27 (37%)	12
Rash	5/27 (18.5%)	7
Skin ulcer	5/27 (18.5%)	5
Urticaria	2/27 (7.4%)	2
Surgical and medical procedures
Wound drainage	2/27 (7.4%)	2
Vascular disorders
Deep vein thrombosis	3/27 (11.1%)	3
Haematoma	2/27 (7.4%)	2
Haemorrhage	2/27 (7.4%)	2
Hypertension	16/27 (59.3%)	17
Hypotension	8/27 (29.6%)	15

Limitations/Caveats

This study was converted to a pilot study on May 23, 2006. Only 27 of the planned 211 participants were enrolled, thus reducing the number of subjects available for analysis.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.