Liver Transplant
Conditions
Keywords
immunosuppression, anti-rejection, immune tolerance
Brief summary
To determine whether long-term maintenance therapy with a single drug (Myfortic) applied using advanced immunologic monitoring tools in selected patients can lead to superior native kidney function at 2 years without resulting in increased acute rejection episodes or deterioration of liver allograft function.
Detailed description
The hypothesis to be tested is that donor-microchimerism in specific cell populations promotes the development of donor-specific regulation which in turn allows for long-term maintenance therapy with a single drug (Myfortic) in selected patients leading to superior long-term outcomes. Subjects will be enrolled post-transplantation and will be liver transplant recipients who meet the eligibility and exclusion criteria. We will use post-transplant monitoring for donor-specific immunologic regulation (DSR+/ DSA negative) to direct the withdrawal of patients to Myfortic monotherapy. Donor microchimerism, DSR, DSA development will be performed on samples obtained every six months from patients on study. The ultimate objective of the study is to use immunologic monitoring to develop a rational approach to achieving individualized immunosuppression for liver transplant patients.
Interventions
DRUGGroup 1 Donor Specific Regulation (DSR) +, Mycophenolic acid (MPA) monotherapy
Group 1 Donor Specific Regulation (DSR) +, MPA monotherapy Mycophenolate sodium : Myfortic therapy will be maintained at a target dose of 720mg BID. Tacrolimus doses will be lowered to achieve levels of 3-5 ng/ml. 6 months later, immunological monitoring will be repeated and tacrolimus will be completely discontinued if the subject remains DSR + without development of donor specific antibodies (DSA). Those who become DSR- or develop DSA will remain on a tacrolimus dose achieving levels of 3-5 ng/ml, and will not undergone any additional reduction. Subjects will be followed for 24 months at 6 month intervals, and will provide health information and blood samples.
OTHERdata and sample collection
Group 2 : Donor specific regulation (DSR) + standard of care: These subjects will be maintained on standard of care immunosuppression consisting of Tacrolimus and Mycophenolate sodium (MPS) with no reduction in tacrolimus dose during the 24 months of study enrollment. Subjects will be followed for 24 months at 6 month intervals, and will provide health information and blood samples
Sponsors
Novartis Pharmaceuticals
University of Wisconsin, Madison
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female subjects, ages 18 years and older who have received a primary liver transplant from a deceased donor for end stage liver disease \*(ESLD). * Women of child-bearing potential must have a negative serum pregnancy test at the time of screening and agree to use a medically acceptable method of contraception throughout the study and for 3 months following discontinuation of study treatment.
Exclusion criteria
* Recipients of multi-organ transplants. * Recipients with positive crossmatch with their donor (current or previously). * Subjects with a screening white blood cell count ≤ 2,000 mm3 or absolute neutrophil count (ANC) ≤ 1000, platelet count ≤ 100,000 mm3. * Recipients with a hematocrit \< 32. * History of malignancy within 5 years of enrollment (except for adequately treated basal cell or squamous cell carcinoma of the skin). * Subjects who are positive for hepatitis C, hepatitis B surface antigen, or HIV. * Subjects with previous intolerance to full dose MPA agent. * Subjects with a history of acute rejection within 6 months prior to study enrollment. * Subjects who have had chronic ductopenic rejection. * Subjects who had rejection in the first-year post-transplant and are less than 3 years post-transplant. * Subjects who had rejection requiring treatment with thymoglobulin or Orthoclone-OKT3 (OKT3) at anytime post-transplant. * Original cause of ESLD related to autoimmune diseases such as autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis. * Subjects who have received an investigational drug within 4 weeks of study entry. * Subjects with a history of a psychological illness or condition such as to interfere with the subject's ability to understand the requirements of the study. * Female subjects who are pregnant or nursing or females who are unwilling to use contraception during the study. * Subjects who are currently receiving any therapy for immunosuppression other than a MPA agent and tacrolimus. * Subjects with a history of hepatocellular carcinoma (T2 \>). * Subjects with severe coexisting disease or presenting with any unstable medical condition which could affect study objectives. * Subjects who have a known hypersensitivity to tacrolimus or mycophenolate
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Modification of Diet in Renal Disease (MDRD) Estimation of Glomerular Filtration Rate (GFR) | 6 months post enrollment/randomization | This outcome measure is used to determine if the reduction of calcineurin inhibitor immunosuppression leads to improved native kidney function. Native kidney function is assessed using the Modification of Diet in Renal Disease (MDRD) estimation of glomerular filtration rate (GFR) from serum or plasma creatinine samples at the reported time points. Reference intervals include: Healthy 18 years and up: 60-120 mL/min/1.73 sqm Chronic kidney disease: GFR \< 60 mL/min/1.73 sqm Kidney failure: GFR \< 15 mL/min/1.73 sqm |
Countries
United States
Participant flow
Pre-assignment details
11 participants consented and were enrolled in the study. However, 2 of the subjects screen failed and did not participate in the study beyond providing their consent to participate. Thus only 9 subjects consented to and started the study and these 9 subjects are analyzed in the results.
Participants by arm
| Arm | Count |
|---|---|
| Group 3: Donor Specific Regulation DSR -, Standard of Care Subjects who test DSR (donor specific regulation) negative will not be randomized to possible tacrolimus withdrawal, and will remain on standard of care immunosuppression.
data and sample collection: Group 3 : DSR(-) standard of care:
These subjects are those who were DSR negative and/or DSA positive at enrollment and therefore are not eligible for the withdrawal aspect of the study. These subjects will be maintained on standard of care immunosuppression consisting of tacrolimus and mycophenolate sodium (MPS) with no reduction in tacrolimus dose during the 24 months of study enrollment. These subjects will be asked to provide heath information and donate blood, exclusively for research testing, at the same 6 month intervals as those in the other two arms of the study, and will be followed for 24 months. | 9 |
| Group 2 Donor Specific Regulation DSR +; Standard of Care Subjects that are DSR (donor specific regulation) positive and randomized (1:1)to Group 2 will remain on standard of care immunosuppression.
data and sample collection: Group 2 : DSR(+) standard of care:
These subjects will be maintained on standard of care immunosuppression consisting of tacrolimus and mycophenolate sodium (MPS) with no reduction in tacrolimus dose during the 24 months of study enrollment.
Subjects will be followed for 24 months at 6 month intervals, and will provide health information and blood samples | 0 |
| Group 1 Donor Specific Regulation (DSR) +, MPA Monotherapy Subjects that are DSR (donor specific regulation) positive and randomized (1:1)to Group 1 will begin a taper off tacrolimus for 6 months, after repeat DSR testing at 6 months subject will either discontinue tacrolimus if they remain DSR negative or remain at reduced dose if converted to DSR positive
Withdrawal of Tacrolimus to mycophenolate monotherapy: Group 1:
Mycophenolate sodium : Myfortic therapy will be maintained at a target dose of 720mg BID.
Tacrolimus doses will be lowered to achieve levels of 3-5 ng/ml. 6 months later, immunological monitoring will be repeated and tacrolimus will be completely discontinued if the subject remains DSR + without development of donor specific antibodies (DSA). Those who become DSR- or develop DSA will remain on a tacrolimus dose achieving levels of 3-5 ng/ml, and will not undergone any additional reduction.
Subjects will be followed for 24 months at 6 month intervals, and will provide health information and blood samples. | 0 |
| Total | 9 |
Baseline characteristics
| Characteristic | Group 3: Donor Specific Regulation DSR -, Standard of Care | Total |
|---|---|---|
| Age, Categorical <=18 years | 0 participants | 0 participants |
| Age, Categorical >=65 years | 1 participants | 1 participants |
| Age, Categorical Between 18 and 65 years | 8 participants | 8 participants |
| Age, Continuous | 51 years STANDARD_DEVIATION 14.757 | 51 years STANDARD_DEVIATION 14.76 |
| Gender Female | 3 participants | 3 participants |
| Gender Male | 6 participants | 6 participants |
| Region of Enrollment United States | 9 participants | 9 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 9 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 9 | 0 / 0 | 0 / 0 |
Outcome results
Primary
Modification of Diet in Renal Disease (MDRD) Estimation of Glomerular Filtration Rate (GFR)
This outcome measure is used to determine if the reduction of calcineurin inhibitor immunosuppression leads to improved native kidney function. Native kidney function is assessed using the Modification of Diet in Renal Disease (MDRD) estimation of glomerular filtration rate (GFR) from serum or plasma creatinine samples at the reported time points. Reference intervals include: Healthy 18 years and up: 60-120 mL/min/1.73 sqm Chronic kidney disease: GFR \< 60 mL/min/1.73 sqm Kidney failure: GFR \< 15 mL/min/1.73 sqm
Time frame: 6 months post enrollment/randomization
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 3: DSR (-), Standard of Care | Modification of Diet in Renal Disease (MDRD) Estimation of Glomerular Filtration Rate (GFR) | 60.14 mL/min/1.73 sqm | Standard Deviation 16.39 |
Primary
Modification of Diet in Renal Disease (MDRD) Estimation of Glomerular Filtration Rate (GFR)
This outcome measure is used to determine if the reduction of calcineurin inhibitor immunosuppression leads to improved native kidney function. Native kidney function is assessed using the Modification of Diet in Renal Disease (MDRD) estimation of glomerular filtration rate (GFR) from serum or plasma creatinine samples at the reported time points. Reference intervals include: Healthy 18 years and up: 60-120 mL/min/1.73 sqm Chronic kidney disease: GFR \< 60 mL/min/1.73 sqm Kidney failure: GFR \< 15 mL/min/1.73 sqm
Time frame: 12 months post enrollment/randomization
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Group 3: DSR (-), Standard of Care | Modification of Diet in Renal Disease (MDRD) Estimation of Glomerular Filtration Rate (GFR) | 82.4 mL/min/1.73 sqm | Standard Deviation 28.34 |