Liver Transplantation
Conditions
Brief summary
The purpose of this investigation is to study if very low dose IL-2, given to liver transplant patients by subcutaneous (under the skin) injections, over a 4 week period of time, will cause an increase in the number of Treg cells in the blood.
Detailed description
A common complication of organ transplantation is 'rejection' of the transplanted organ. This occurs when the body's immune system tries to attack (or reject) the transplanted organ. Drugs known as immunosuppressants (anti-rejection medications) are prescribed for patients after transplantation to prevent rejection. But, anti-rejection medications are associated with significant side effects including high blood pressure, high blood sugars, and high cholesterol - all of which may increase the risk of heart and vascular complications. Anti-rejection medications also increase the long-term risk of some types of cancer. Sometimes, liver transplant patients who stop taking anti-rejection medications do not experience rejection of their transplanted liver and the liver keeps working. These patients are said to tolerate the transplanted liver, and this condition is referred to as tolerance. Doctors are working to learn more about why some liver transplant patients develop tolerance after receiving a transplant, while others do not. Studies have shown that patients who develop tolerance have an increase in a type of immune cell called regulatory T-cells or Tregs. This means Tregs may be important in preventing rejection of a transplanted organ. Studies have also shown that a human cytokine (a type of protein), called interleukin-2 (IL-2) aids in increasing the number of Treg cells in the body, and IL-2 has been given to patients to successfully treat disorders of the immune system such as graft vs host disease - a serious condition sometimes seen in patients after bone marrow transplantation. The purpose of this investigation is to study if low dose IL-2, given to liver transplant patients by subcutaneous (under the skin) injections, over a 4 week period of time, will cause an increase in the number of Treg cells in the blood. In addition, investigators will learn about the kinds of side effects low dose IL-2 will cause and how severe those side effects will be.
Interventions
BIOLOGICALInterleukin-2
Subjects will self-administer low dose IL-2 as subQ injection (0.30 MIU per meter squared body surface area) for 4 weeks.
Sponsors
Beth Israel Deaconess Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Adult liver transplant recipients 2-4 years post transplantation 2. Male or female adult, age 18 - 65 years 3. Stable dosage of suppressant therapy for 1 month prior to study.
Exclusion criteria
1. Recipient of multiple transplants (including solid organ, stem-cell, and bone marrow) 2. Serum liver panel (ALT, AST, Alkaline Phosphatase and Total Bilirubin) \> 2 x ULN, 3. Serum creatinine \> 1.5 x ULN, 4. eGFR of \< 40 ml/min, 5. Detectable hepatitis viral load, 6. Abnormal ECG with clinically significant findings per study physician's judgement, 7. Active infection, 8. Presence or history of autoimmunity disorders, 9. Evidence of allograft rejection, 10. Liver biopsy or fibroscan evidence of advanced stage liver fibrosis (\> Stage 2 Fibrosis), 11. Presence or history of cardiac or pulmonary disease, 12. Pregnant or nursing (lactating) women, 13. Health condition precludes participation in trial at study physician's judgment, 14. Inability to give consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Regulatory T-Cell Count | baseline, week 2, week 4, week8, week12 | Peripheral Blood Mononuclear Cell Flow Cytometry |
| % Increase in CD4 Tregs | baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks | % CD4 T Regs were measured at several time points after IL-2 administration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Differential Immune Cell Count | baseline, 2 weeks, 4 weeks, 8 weeks, 12 Weeks | Peripheral Blood Mononuclear Cell Flow Cytometry |
Other
| Measure | Time frame | Description |
|---|---|---|
| Kidney Function Serum Panel (> 1.5 x Upper Limit Normal) | 2 weeks, 4 weeks, 8 weeks, 12 weeks, 36 weeks | Number of participants with a serum creatinine \> 1.5 x upper limit of normal through week 36 |
| Liver Function Serum Panel (> 2 x Upper Limit Normal) | week 2, 4 week, week 8, week12, week36 | Number of patients with a serum amino alaninetransferase \> 2 x upper limit of normal through week 36 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Open Label. Active Study Treatment Arm IL-2 (Interleukin-2; Aldesleukin; Proleukin) administered daily as a single subcutaneous injection 0.30 MIU per meter squared body surface area for a duration of 4 weeks. | 6 |
| Total | 6 |
Baseline characteristics
| Characteristic | Open Label. Active Study Treatment Arm |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants |
| Age, Continuous | 54 years |
| Alanine aminotransferase (ALT) | 19 units of ALT/L |
| CD19 B cells (%PBMC) | 4.84 %PBMC |
| CD3T cells (%PBMC) | 53.74 %PBMC |
| CD4 conventional T cells (% of CD4 cells) | 97.34 %PBMC |
| CD4 T cells (% PBMC) | 25.29 %PBMC |
| CD4 Treg cells (% CD4 T cells) | 2.13 %PBMC |
| CD4Treg (% of PBMC) | 0.44 %PBMC |
| CD56 NK (%PBMC) | 6.37 %PBMC |
| CD8 T cells (%PBMC) | 28.05 %PBMC |
| Hematocrit | 39 % |
| Monocyte/Dendritic cells (% PBMC) | 12.82 %PBMC |
| NKT (%PBMC) | 13.56 %PBMC |
| Platelet count | 162,000 platelets /uL |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 4 Participants |
| Region of Enrollment United States | 6 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 4 Participants |
| Time from transplant | 2.85 years |
| White Blood Cell count (WBC) | 5.85 cells *10^9/L |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 6 |
| other Total, other adverse events | 6 / 6 |
| serious Total, serious adverse events | 1 / 6 |
Outcome results
Primary
% Increase in CD4 Tregs
% CD4 T Regs were measured at several time points after IL-2 administration.
Time frame: baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label. Active Study Treatment Arm | % Increase in CD4 Tregs | Baseline CD4Treg (%CD4Tcells) | 2.13 percentage of CD4 T cells |
| Open Label. Active Study Treatment Arm | % Increase in CD4 Tregs | Wk2 CD4Treg (%CD4Tcells) | 13.15 percentage of CD4 T cells |
| Open Label. Active Study Treatment Arm | % Increase in CD4 Tregs | Wk4 CD4Treg (%CD4Tcells) | 11.93 percentage of CD4 T cells |
| Open Label. Active Study Treatment Arm | % Increase in CD4 Tregs | Wk8 CD4Treg(%CD4Tcells) | 2.79 percentage of CD4 T cells |
| Open Label. Active Study Treatment Arm | % Increase in CD4 Tregs | Wk12 CD4Treg (%CD4Tcells) | 2.63 percentage of CD4 T cells |
Primary
Regulatory T-Cell Count
Peripheral Blood Mononuclear Cell Flow Cytometry
Time frame: baseline, week 2, week 4, week8, week12
Population: The efficacy analysis was performed on 5 patients. 1 patient withdrew from the study due to an adverse event before any efficacy data was obtained.6 patients were enrolled, 66% male with a median age of 54 years. Median time from transplant was 2.8 years. Five patients were on tacrolimus monotherapy and 1 patients was on tacrolimus and mycophenolate mofetil.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label. Active Study Treatment Arm | Regulatory T-Cell Count | Baseline CD4Tred (%PBMC) | 0.44 percentage of PBMC |
| Open Label. Active Study Treatment Arm | Regulatory T-Cell Count | Wk2 CD4Treg (%PBMC) | 3.71 percentage of PBMC |
| Open Label. Active Study Treatment Arm | Regulatory T-Cell Count | Wk4 CD4Treg (%PBMC) | 3.57 percentage of PBMC |
| Open Label. Active Study Treatment Arm | Regulatory T-Cell Count | Wk8 CD4Treg (%PBMC) | 0.6 percentage of PBMC |
| Open Label. Active Study Treatment Arm | Regulatory T-Cell Count | Wk12 CD4Treg (%PBMC) | 0.64 percentage of PBMC |
Comparison: This is an open label feasibility study to assess the efficacy and safety of a 4 week course of daily subcutaneous IL-2 injections to increase peripheral blood CD4 Tregs. Results are expressed as median, IQR and comparison were performed using one way or two-way ANOVA, followed by Tukey's multiple comparison test. For all comparisons, a p\< 0.05 was considered significant.p-value: <0.01ANOVA
Secondary
Differential Immune Cell Count
Peripheral Blood Mononuclear Cell Flow Cytometry
Time frame: baseline, 2 weeks, 4 weeks, 8 weeks, 12 Weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Baseline CD3Tcells (%PBMC) | 53.74 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk2 CD3Tcells (%PBMC) | 57.05 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk4 CD3Tcells (%PBMC) | 53.69 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk8 CD3Tcells (%PBMC) | 58.00 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk12 CD3 Tcells (%PBMC) | 53.35 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Baseline CD4Tcells (%PBMC) | 25.59 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk2 CD4Tcells (%PBMC) | 23.7 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk4 CD4Tcells (%PBMC) | 26.11 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk8 CD4Tcells (%PBMC) | 26.91 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk12 CD4Tcells (%PBMC) | 26.08 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Baseline CD8Tcells (%PBMC) | 28.05 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk2 CD8Tcells (%PBMC) | 22.9 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk4 CD8Tcells (%PBMC) | 22.9 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk8 CD8Tcells (%PBMC) | 24.88 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk12 CD8Tcells (%PBMC) | 23.23 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Baseline CD19Bcells (%PBMC) | 4.84 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk2 CD19Bcells (%PBMC) | 4.84 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk4 CD19Bcells (%PBMC) | 3.63 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk8 CD19Bcells (%PBMC) | 6.16 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk12 CD19Bcells (%PBMC) | 6.63 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Baseline CD56NKcells (%PBMC) | 6.37 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk2 CD56NKcells (%PBMC) | 12.53 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk4 CD56NKcells (%PBMC) | 11.72 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk8 CD56NKcells (%PBMC) | 6.95 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk12 CD56NKcells (%PBMC) | 6.09 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Baseline NKTcells (%PBMC) | 13.56 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk2 NKTcells (%PBMC) | 11.75 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk4 NKTcells (%PBMC) | 9.33 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk8 NKTcells (%PBMC) | 10.69 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk12 NKTcells (%PBMC) | 11.58 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Baseline Monocytes/Dendritic | 12.82 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk2 Monocytes/Dendritic cells (%PBMC) | 9.00 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk4 Monocytes/Dendritic (%PBMC) | 12.87 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk8 Monocytes/Dendritic (%PBMC) | 11.77 percentage of PMBC |
| Open Label. Active Study Treatment Arm | Differential Immune Cell Count | Wk12 Monocytes/Dendritic (%PBMC) | 12.35 percentage of PMBC |
Other Pre-specified
Kidney Function Serum Panel (> 1.5 x Upper Limit Normal)
Number of participants with a serum creatinine \> 1.5 x upper limit of normal through week 36
Time frame: 2 weeks, 4 weeks, 8 weeks, 12 weeks, 36 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Open Label. Active Study Treatment Arm | Kidney Function Serum Panel (> 1.5 x Upper Limit Normal) | Week 2 | 1 Participants |
| Open Label. Active Study Treatment Arm | Kidney Function Serum Panel (> 1.5 x Upper Limit Normal) | week 4 | 0 Participants |
| Open Label. Active Study Treatment Arm | Kidney Function Serum Panel (> 1.5 x Upper Limit Normal) | week 8 | 0 Participants |
| Open Label. Active Study Treatment Arm | Kidney Function Serum Panel (> 1.5 x Upper Limit Normal) | week 12 | 0 Participants |
| Open Label. Active Study Treatment Arm | Kidney Function Serum Panel (> 1.5 x Upper Limit Normal) | week 36 | 0 Participants |
Other Pre-specified
Liver Function Serum Panel (> 2 x Upper Limit Normal)
Number of patients with a serum amino alaninetransferase \> 2 x upper limit of normal through week 36
Time frame: week 2, 4 week, week 8, week12, week36
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Open Label. Active Study Treatment Arm | Liver Function Serum Panel (> 2 x Upper Limit Normal) | weeks 12 | 0 Participants |
| Open Label. Active Study Treatment Arm | Liver Function Serum Panel (> 2 x Upper Limit Normal) | week 2 | 0 Participants |
| Open Label. Active Study Treatment Arm | Liver Function Serum Panel (> 2 x Upper Limit Normal) | week 4 | 0 Participants |
| Open Label. Active Study Treatment Arm | Liver Function Serum Panel (> 2 x Upper Limit Normal) | week 8 | 0 Participants |
| Open Label. Active Study Treatment Arm | Liver Function Serum Panel (> 2 x Upper Limit Normal) | week 36 | 0 Participants |