Mycophenolate Mofetil Immunosuppression Without/With Reduced Dose Calcineurin Inhibitor Long After Liver Transplantation

• Sponsor: Albert Einstein Healthcare Network (Other)
• Overall Status: Completed
• CT.gov ID: NCT00206076
• Collaborator: Hoffmann-La Roche (Industry)
• Enrollment: 19
• Locations: 3
• Arms: 2
• Duration (Months): 34
• Patients Per Site: 6.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of the study is to assess the safety and efficacy of mycophenolate mofetil alone, or with reduced dose cyclosporine (CsA) or tacrolimus, for immunosuppression long-term after liver transplantation, in an attempt to reduce the potential side effects from using cyclosporine or tacrolimus.

Condition or Disease	Intervention/Treatment	Phase
Liver Disease	Drug: mycophenolate mofetil; Drug: mycophenolate mofetil	Phase 4

Detailed Description

Most liver transplant recipients receive an immunosuppressive drug regimen that contains either cyclosporine or tacrolimus. Although these drugs have revolutionized transplantation, in many patients their long-term use is a major cause of serious side effects, including kidney failure, hypertension, diabetes mellitus, hyperlipidemia, and/or neurologic side effects. Stopping or reducing the dose of cyclosporine or tacrolimus can ameliorate the above side effects but may increase the risk of rejection. Mycophenolate mofetil (MMF), a safe and effective immunosuppressant that does not cause the above side effects, is typically used in combination with cyclosporine or tacrolimus. Attempts in liver transplant recipients at using mycophenolate mofetil alone or with reduced dose cyclosporine or tacrolimus have been successful but some patients developed rejection, and a few patients suffered liver failure. Most rejections after liver transplantation are easy to successfully treat with increased immunosuppression, but such treatment may carry risks such as increased susceptibility to infection. There have not yet been any large trials to adequately assess the safety and efficacy of using mycophenolate mofetil this way (alone or with reduced dose calcineurin inhibitor (CNI)).

The purpose of this trial is to evaluate whether mycophenolate mofetil as monotherapy or with reduced dose cyclosporine or tacrolimus long-term after liver transplantation is safe and decreases side effects related to calcineurin inhibitor use.

Only liver recipients expected to have a relatively low risk of developing rejection and/or liver failure are eligible for this trial. Some reasons for considering them low risk are their stable liver function, having had the transplant for over a year, having had one or fewer prior rejection episodes, having had non-autoimmune liver disease, their currently requiring low dose/level cyclosporine or tacrolimus, and the plan to use high dose mycophenolate mofetil and to exclude patients that fail to attain target values for mycophenolic acid area under the concentration-time curve (MPA AUC - MycoPhenolic Acid Area Under the Curve).

Eligible patients will be randomized to receive either mycophenolate mofetil monotherapy (MMF; CNI discontinued), or mycophenolate mofetil and half their baseline dose of calcineurin inhibitor (MMF; CNI decreased). The primary outcome is biopsy proven rejection and the secondary outcomes include patient and graft survival, adverse events, hepatic profile, blood pressure, renal function, diabetes, and lipid profile. Additionally, mycophenolic acid concentrations will be measured; a mycophenolate mofetil monotherapy trial provides unique opportunity to study the implications of such monitoring. Patients will be followed for 12 months; there will be 16 visits during the trial.

Study Design

• Study Type: Interventional
• Actual Enrollment: 19 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: CellCept (Mycophenolate Mofetil, MMF) Maintenance Immunosuppression in Liver Transplant Recipients With Long-term Follow-up Post-transplantation for Non-Autoimmune Liver Disease - A Prospective, Randomized, Multicenter Trial.
• Study Start Date: Aug 1, 2006
• Actual Primary Completion Date: Jun 1, 2009
• Actual Study Completion Date: Jun 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 mycophenolate mofetil monotherapy	Drug: mycophenolate mofetil; mycophenolate mofetil monotherapy
Active Comparator: 2 mycophenolate mofetil and half their baseline dose of calcineurin inhibitor	Drug: mycophenolate mofetil; mycophenolate mofetil and half their baseline dose of calcineurin inhibitor

Outcome Measures

Primary Outcome Measures

1. Number of Biopsy Proven Rejections at 12 Months [12 months]

   assessed by liver biopsy using Banff International Consensus Schema

Secondary Outcome Measures

1. Patient and Graft Survival at 12 Months [12 months]

2. Number of Participants With Adverse Events Including Infections at 12 Months [12 months]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Male or female 18 years of age or older (females who can become pregnant must use two acceptable methods of birth control while taking mycophenolate mofetil)

• Orthotopic liver transplant more than one year prior to enrollment

• Using calcineurin inhibitor to prevent rejection at time of screening

• Patients must be willing to provide informed consent and abide by the requirements of the study

Exclusion Criteria:

• Liver disease may not have been secondary to an autoimmune cause, including:

• autoimmune hepatitis,

• primary sclerosing cholangitis,

• primary biliary cirrhosis

• Patients who have had:

• more than one prior episode of rejection,

• rejection within the past six months,

• any corticosteroid resistant rejection

• Patients with a tacrolimus trough level of greater than 7 ng/ml within 90 days prior to enrollment

• Patients with a cyclosporine trough level greater than 225 ng/ml within 90 days prior to enrollment

• Patients taking more the 5 mg per day of prednisone within 90 days prior to enrollment

• Patients taking any prednisone within 30 days of enrollment

• Allograft dysfunction within 6 months of enrollment, including ALT and/or total bilirubin greater than 2x normal, and/or biopsy proven hepatitis C virus (HCV) with fibrosis greater than stage II

• White blood cell count less than 2,500 or platelet count less than 50,000 within 60 days of enrollment

• MPA AUC threshold: Patients are not eligible for the study if they do not attain the threshold value MPA AUC (>30 mgh/L if on CsA, >40 mgh/L if on tacrolimus) after 50% calcineurin inhibitor reduction, measured using a 3-sample estimate (trough, 30-min, 120-min)

• Patients who have had a previous transplant of organ(s) other than liver

• Patients who received a liver from a hepatitis C positive donor

• Patients who received a liver from a living donor

• Patients with any technical complication requiring intervention within the three months prior to screening

• Current infection requiring treatment

• History of post transplant lymphoproliferative disorder

• History of malignancy other than non-melanoma skin cancer or Stage 1-2 hepatoma

• Active or unhealed duodenal ulcer

• Concomitant treatment with rapamycin and/or interferon

• Known allergy or sensitivity to CellCept® or any of its components

• Unable or unwilling to comply with the protocol requirements or considered by the investigator(s) to be unfit for the study

• Participation in a clinical trial within 30 days prior to study entry or prior enrollment in any CellCept® clinical trial

• Pregnant or breastfeeding woman

• Diabetes with known, clinically significant gastroparesis

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Kentucky at Lexington	Lexington	Kentucky	United States
2	Albert Einstein Medical Center	Philadelphia	Pennsylvania	United States	19141
3	Texas Transplant Institute	San Antonio	Texas	United States

Sponsors and Collaborators

• Albert Einstein Healthcare Network
• Hoffmann-La Roche

Investigators

• Principal Investigator: David J Reich, MD, Drexel College of Medicine

Study Documents (Full-Text)

None provided.

More Information

Publications

• Fraser GM, Grammoustianos K, Reddy J, Rolles K, Davidson B, Burroughs AK. Long-term immunosuppression without corticosteroids after orthotopic liver transplantation: a positive therapeutic aim. Liver Transpl Surg. 1996 Nov;2(6):411-7.
• Herrero JI, Quiroga J, Sangro B, Girala M, Gómez-Manero N, Pardo F, Alvárez-Cienfuegos J, Prieto J. Conversion of liver transplant recipients on cyclosporine with renal impairment to mycophenolate mofetil. Liver Transpl Surg. 1999 Sep;5(5):414-20.
• Hodge EE, Reich DJ, Clavien PA, Kim-Schluger L. Use of mycophenolate mofetil in liver transplant recipients experiencing renal dysfunction on cyclosporine or tacrolimus-randomized, prospective, multicenter study results. Transplant Proc. 2002 Aug;34(5):1546-7.
• Mazariegos GV, Reyes J, Marino IR, Demetris AJ, Flynn B, Irish W, McMichael J, Fung JJ, Starzl TE. Weaning of immunosuppression in liver transplant recipients. Transplantation. 1997 Jan 27;63(2):243-9.
• McDiarmid SV, Farmer DA, Goldstein LI, Martin P, Vargas J, Tipton JR, Simmons F, Busuttil RW. A randomized prospective trial of steroid withdrawal after liver transplantation. Transplantation. 1995 Dec 27;60(12):1443-50.
• Munoz SJ, Rothstein KD, Reich D, Manzarbeitia C. Long-term care of the liver transplant recipient. Clin Liver Dis. 2000 Aug;4(3):691-710. Review.
• Raimondo ML, Dagher L, Papatheodoridis GV, Rolando N, Patch DW, Davidson BR, Rolles K, Burroughs AK. Long-term mycophenolate mofetil monotherapy in combination with calcineurin inhibitors for chronic renal dysfunction after liver transplantation. Transplantation. 2003 Jan 27;75(2):186-90.
• Reich D, Rothstein K, Manzarbeitia C, Muñoz S. Common medical diseases after liver transplantation. Semin Gastrointest Dis. 1998 Jul;9(3):110-25. Review.
• Reich DJ, Clavien PA, Hodge EE; MMF Renal Dysfunction after Liver Transplantation Working Group. Mycophenolate mofetil for renal dysfunction in liver transplant recipients on cyclosporine or tacrolimus: randomized, prospective, multicenter pilot study results. Transplantation. 2005 Jul 15;80(1):18-25.
• Schlitt HJ, Barkmann A, Böker KH, Schmidt HH, Emmanouilidis N, Rosenau J, Bahr MJ, Tusch G, Manns MP, Nashan B, Klempnauer J. Replacement of calcineurin inhibitors with mycophenolate mofetil in liver-transplant patients with renal dysfunction: a randomised controlled study. Lancet. 2001 Feb 24;357(9256):587-91.
• Shaw LM, Korecka M, Venkataramanan R, Goldberg L, Bloom R, Brayman KL. Mycophenolic acid pharmacodynamics and pharmacokinetics provide a basis for rational monitoring strategies. Am J Transplant. 2003 May;3(5):534-42. Review.
• Stegall MD, Everson GT, Schroter G, Karrer F, Bilir B, Sternberg T, Shrestha R, Wachs M, Kam I. Prednisone withdrawal late after adult liver transplantation reduces diabetes, hypertension, and hypercholesterolemia without causing graft loss. Hepatology. 1997 Jan;25(1):173-7.
• Stewart SF, Hudson M, Talbot D, Manas D, Day CP. Mycophenolate mofetil monotherapy in liver transplantation. Lancet. 2001 Feb 24;357(9256):609-10.
• Wiesner R, Rabkin J, Klintmalm G, McDiarmid S, Langnas A, Punch J, McMaster P, Kalayoglu M, Levy G, Freeman R, Bismuth H, Neuhaus P, Mamelok R, Wang W. A randomized double-blind comparative study of mycophenolate mofetil and azathioprine in combination with cyclosporine and corticosteroids in primary liver transplant recipients. Liver Transpl. 2001 May;7(5):442-50.

• Responsible Party: Albert Einstein Healthcare Network
• ClinicalTrials.gov Identifier: NCT00206076
• Other Study ID Numbers: CEL350
• First Posted: Sep 21, 2005
• Last Update Posted: Aug 2, 2013
• Last Verified: Jul 1, 2013

• Keywords provided by Albert Einstein Healthcare Network: Liver transplantation; Calcineurin inhibitor withdraw; mycophenolate mofetil; Immunosuppression side effects; Graft rejection
• Additional relevant MeSH terms: Liver Diseases; Mycophenolic Acid

Study Results

Participant Flow

Recruitment Details	Participants were current patients from 3 outpatient transplant offices and recruited between July 2006 and May 2008.
Pre-assignment Detail	Participants were screened over a 2 week period. Three participants withdrew consent after signing the consent form. One participant failed screening (didn't attain threshold MPA level). These subjects were excluded from the trial before assignment to groups.

Arm/Group Title	MMF, CNI Discontinued	MMF; CNI Decreased
Arm/Group Description	Received Mycophenolate Mofetil (MMF); Complete withdrawal of calcineurin inhibitors (CNI)	Received Mycophenolate Mofetil (MMF); calcineurin inhibitors (CNI) decreased to 50% of pre-enrollment dosage
Period Title: Overall Study
STARTED	9	10
COMPLETED	6	9
NOT COMPLETED	3	1

Baseline Characteristics

Arm/Group Title	MMF, CNI Discontinued	MMF; CNI Decreased	Total
Arm/Group Description	Received Mycophenolate Mofetil (MMF); Complete withdrawal of calcineurin inhibitors (CNI)	Received Mycophenolate Mofetil (MMF); calcineurin inhibitors (CNI) decreased to 50% of pre-enrollment dosage	Total of all reporting groups
Overall Participants	9	10	19
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	7 77.8%	10 100%	17 89.5%
>=65 years	2 22.2%	0 0%	2 10.5%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.11 (8.46)	54.6 (7.26)	55.32 (7.67)
Sex: Female, Male (Count of Participants)
Female	2 22.2%	3 30%	5 26.3%
Male	7 77.8%	7 70%	14 73.7%
Region of Enrollment (participants) [Number]
United States	9 100%	10 100%	19 100%

Outcome Measures

1. Primary Outcome

Title	Number of Biopsy Proven Rejections at 12 Months
Description	assessed by liver biopsy using Banff International Consensus Schema
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MMF, CNI Discontinued	MMF; CNI Decreased
Arm/Group Description	Received Mycophenolate Mofetil (MMF); Complete withdrawal of calcineurin inhibitors (CNI)	Received Mycophenolate Mofetil (MMF); calcineurin inhibitors (CNI) decreased to 50% of pre-enrollment dosage
Measure Participants	6	9
Number [participants]	0 0%	0 0%

2. Secondary Outcome

Title	Patient and Graft Survival at 12 Months
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

everyone enrolled who completed the study

Arm/Group Title	CNI Discontinued	CNI Reduction
Arm/Group Description	complete withdrawal of calcineurin inhibitors (CNI)	calcineurin inhibitors (CNI) decreased to 50% of pre-enrollment
Measure Participants	6	9
Number [participants]	6 66.7%	9 90%

3. Secondary Outcome

Title	Number of Participants With Adverse Events Including Infections at 12 Months
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

everyone enrolled who completed the study

Arm/Group Title	MMF, CNI Discontinued	MMF; CNI Decreased
Arm/Group Description	Received Mycophenolate Mofetil (MMF); Complete withdrawal of calcineurin inhibitors (CNI)	Received Mycophenolate Mofetil (MMF); calcineurin inhibitors (CNI) decreased to 50% of pre-enrollment dosage
Measure Participants	6	9
Number [participants]	2 22.2%	1 10%

Adverse Events

Arm/Group Title	MMF, CNI Discontinued		MMF; CNI Decreased
Arm/Group Description	Received Mycophenolate Mofetil (MMF); Complete withdrawal of calcineurin inhibitors (CNI)		Received Mycophenolate Mofetil (MMF); calcineurin inhibitors (CNI) decreased to 50% of pre-enrollment dosage
All Cause Mortality
	MMF, CNI Discontinued		MMF; CNI Decreased
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	MMF, CNI Discontinued		MMF; CNI Decreased
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/9 (22.2%)		1/10 (10%)
Blood and lymphatic system disorders
change in white blood cell count	0/9 (0%)	0	1/10 (10%)	1
Gastrointestinal disorders
Nausea	1/9 (11.1%)	1	0/10 (0%)	0
Constipation alter with diarrhea	1/9 (11.1%)	1	0/10 (0%)	0
diarrhea	1/9 (11.1%)	1	0/10 (0%)	0
gastroenteritis	0/9 (0%)	0	1/10 (10%)	1
Other (Not Including Serious) Adverse Events
	MMF, CNI Discontinued		MMF; CNI Decreased
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/9 (100%)		7/10 (70%)
Gastrointestinal disorders
Diarrhea	6/9 (66.7%)	8	6/10 (60%)	6
Nausea	2/9 (22.2%)	2	3/10 (30%)	4
Hepatobiliary disorders
Increased liver enzymes	2/9 (22.2%)	3	1/10 (10%)	3
Respiratory, thoracic and mediastinal disorders
Cough	2/9 (22.2%)	3	2/10 (20%)	3
Nasal congestion	1/9 (11.1%)	1	3/10 (30%)	4

Limitations/Caveats

[Not Specified]

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.