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| Name | Class |
|---|---|
| Astellas Pharma Canada, Inc. | INDUSTRY |
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While the incidence of acute rejection and early graft loss have improved dramatically with the advent of newer immunosuppressant medications, improvements in long-term patient and allograft survival after kidney transplantation have not been achieved. The specific drug combination that provides the best outcomes with the least amount of side effects is not known. Each kidney transplant center uses the combination of drugs that they believe is optimal. This study is about identifying whether drugs that are currently approved for use in kidney transplantation can be used in a new combination safely and with potentially fewer side effects than the drug combinations that are currently used at St. Paul's Hospital and other transplant centres.
Purpose This study has been designed to test whether using Thymoglobulin with low dose tacrolimus and early steroid withdrawal will minimize both kidney rejection and the development of new onset diabetes after transplant (NODAT).
Justification Experimental treatment is low target tacrolimus with thymoglobulin. Standard treatment is a standard target (higher dose) tacrolimus and basiliximab, instead of thymoglobulin.
The investigators hypothesize, that a combined approach of early steroid withdrawal and low dose tacrolimus in low immunologic risk transplant recipients will be effective in reducing the incidence of new onset diabetes mellitus, while maintaining a low risk of acute rejection.
Objective
The objective of this study is to compare early post-transplant outcomes with the use of low target versus standard target Advagraf in de novo kidney allograft recipients of low immunologic risk undergoing early corticosteroid withdrawal.
Research Method
This is a pilot study. Primary and secondary outcomes are as follows:
Primary Outcome Composite endpoint of biopsy proven acute rejection and NODAT at 6 months post transplantation.
Secondary Outcomes
The primary endpoint will be evaluated by time-to-event Kaplan Meier analysis and by Chi-squared analysis of final 6 month data.
Statistical Analysis
Sample size and power:
In the setting of early steroid withdrawal, Woodle et al. reported an acute rejection rate of 14% with rATG and 24% with an interleukin-2 receptor antibody induction(10). The incidence of NODAT was reported at 21% by Woodle, et al., and was reported 10% in the low dose tacrolimus arm of the ELITE-Symphony trial. The investigators, therefore expect a combined event rate of 24% in Group A and 45% in group B. With a power of 0.80 and alpha error of 0.05, the investigators determined that the investigators need 72 subjects in each arm to demonstrate a 20% difference in our composite primary outcome. For this initial pilot study, the investigators aim to recruit a total of 30 subjects After receiving informed consent, subjects will be randomized on a 1:1 basis to one of the two treatment groups. Subjects who discontinue the study prematurely will not be replaced.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Low target tacrolimus (Advagraf) | Experimental | This group will receive rabbit anti-thymocyte globulin (rATG) induction (3 -4 doses of 1.5 mg/kg during the first post transplant week) with IV solumedrol, MPA (Mycophenolate Mofetil or Mycophenolate Sodium), and "low-target" Advagraf. |
|
| Standard target tacrolimus (Advagraf) | Active Comparator | This group will receive basiliximab induction (40 mg total) with IV solumedrol, MPA (Mycophenolate Mofetil or Mycophenolate Sodium), and "standard target" Advagraf. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tacrolimus | Drug | Low target tacrolimus Advagraf (0.25mg/kg) orally once daily dosed as per manufacturer's recommendation to target trough levels as per Table 1 Table 1 Months post tx: 0-1 month, level 5-7; 1-3 months, level 4-5; and 3-6 months, level 3-4 |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With New Onset Diabetes After Transplant (NODAT) or Acute Rejection | Composite endpoint of biopsy proven acute rejection and NODAT at 6 months post transplantation. NODAT will be defined as either FPG >7.0mmol/L OR symptoms of hyperglycemia and a random plasma glucose of >11.1 OR 2-h plasma glucose >11.1 during an oral glucose tolerance test(OGTT). | 6 months post transplant |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participant Deaths | Death of any participant by end of study. | 6 months post transplant |
| Number of Participants With Graft Failure | Any graft failure by the end of the study. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jagbir Gill, MD | UBC / Dept of Medicine / Nephrology | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| St. Paul's Hospital | Vancouver | British Columbia | V6Z 1Y6 | Canada |
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| ID | Title | Description |
|---|---|---|
| FG000 | Low Target Tacrolimus (Advagraf) | This group will receive rabbit anti-thymocyte globulin (rATG) induction (3 -4 doses of 1.5 mg/kg during the first post transplant week) with IV solumedrol, MPA (Mycophenolate Mofetil or Mycophenolate Sodium), and "low-target" Advagraf. Tacrolimus: Low target tacrolimus Advagraf (0.25mg/kg) orally once daily dosed as per manufacturer's recommendation to target trough levels as per Table 1 Table 1 Months post tx: 0-1 month, level 5-7; 1-3 months, level 4-5; and 3-6 months, level 3-4 |
| FG001 | Standard Target Tacrolimus (Advagraf) | This group will receive basiliximab induction (40 mg total) with IV solumedrol, MPA (Mycophenolate Mofetil or Mycophenolate Sodium), and "standard target" Advagraf. Tacrolimus: Standard dose of tacrolimus Advagraf (0.25mg/kg) orally once daily dosed as per manufacturer's recommendation to target trough levels as per Table 1 Table 1 Months post tx 0-1 month; level 8-12; 1-3 months, level 6-9; and 3-6 months, level 5-8. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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The discrepancy in the Baseline Analysis Population Description and the Overall Number of Baseline Participants is seen because 28 participants in total completed their baseline assessments.
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| ID | Title | Description |
|---|---|---|
| BG000 | Low Target Tacrolimus (Advagraf) | This group will receive rabbit anti-thymocyte globulin (rATG) induction (3 -4 doses of 1.5 mg/kg during the first post transplant week) with IV solumedrol, MPA (Mycophenolate Mofetil or Mycophenolate Sodium), and "low-target" Advagraf. Tacrolimus: Low target tacrolimus Advagraf (0.25mg/kg) orally once daily dosed as per manufacturer's recommendation to target trough levels as per Table 1 Table 1 Months post tx: 0-1 month, level 5-7; 1-3 months, level 4-5; and 3-6 months, level 3-4 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Median |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number of Participants With New Onset Diabetes After Transplant (NODAT) or Acute Rejection | Composite endpoint of biopsy proven acute rejection and NODAT at 6 months post transplantation. NODAT will be defined as either FPG >7.0mmol/L OR symptoms of hyperglycemia and a random plasma glucose of >11.1 OR 2-h plasma glucose >11.1 during an oral glucose tolerance test(OGTT). | The discrepancy in the overall number of participants with outcome measure data and the overall number of participants in the participant flow module is seen because 28 participants in total have outcome measure data available. | Posted | Count of Participants | Participants | 6 months post transplant |
|
Adverse event data was collected from the baseline visit until 6 months post transplant.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Low Target Tacrolimus (Advagraf) | This group will receive rabbit anti-thymocyte globulin (rATG) induction (3 -4 doses of 1.5 mg/kg during the first post transplant week) with IV solumedrol, MPA (Mycophenolate Mofetil or Mycophenolate Sodium), and "low-target" Advagraf. Tacrolimus: Low target tacrolimus Advagraf (0.25mg/kg) orally once daily dosed as per manufacturer's recommendation to target trough levels as per Table 1 Table 1 Months post tx: 0-1 month, level 5-7; 1-3 months, level 4-5; and 3-6 months, level 3-4 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dialysis | Renal and urinary disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Jagbir Gill | St. Paul's Hospital | 6046822344 | 64706 | JAGill@providencehealth.bc.ca |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Aug 3, 2017 | Nov 27, 2019 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| ID | Term |
|---|---|
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
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| ID | Term |
|---|---|
| D016559 | Tacrolimus |
| ID | Term |
|---|---|
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
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|
| Tacrolimus | Drug | Standard dose of tacrolimus Advagraf (0.25mg/kg) orally once daily dosed as per manufacturer's recommendation to target trough levels as per Table 1 Table 1 Months post tx 0-1 month; level 8-12; 1-3 months, level 6-9; and 3-6 months, level 5-8. |
|
|
| 6 months post transplant |
| Number of Participants With Dialysis Events | Any dialysis required by end of study. | 6 months post transplant |
| Number of Participants With Infection Events | Any infection (CMV, opportunistic infections including urinary tract infections requiring treatment, pneumonia) by end of study. | 6 months post transplant |
| Number of Participants With Hospitalization Events | Any hospitalization by end of study. | 6 months post transplant |
| Number of Participants With Malignancy Events | Any malignancy (including post-transplant lymphoproliferative disease) by end of study. | 6 months post transplant |
| Number of Participants With Cardiovascular Event | Any cardiovascular events by end of study. | 6 months post transplant |
| Number of Any Leukopenia Events | Any leukopenia by end of study. | 6 months post transplant |
| Number of Leukopenia Events on ≥2 Occasions | Any leukopenia on ≥2 occasions by end of study. | 6 months post transplant |
| Change From Baseline in Weight | Any changes in weight by end of study. | baseline to 6 months post transplant |
| eGFR at 6 Months | Participant eGFR value by end of study. | 6 months post transplant |
| BG001 | Standard Target Tacrolimus (Advagraf) | This group will receive basiliximab induction (40 mg total) with IV solumedrol, MPA (Mycophenolate Mofetil or Mycophenolate Sodium), and "standard target" Advagraf. Tacrolimus: Standard dose of tacrolimus Advagraf (0.25mg/kg) orally once daily dosed as per manufacturer's recommendation to target trough levels as per Table 1 Table 1 Months post tx 0-1 month; level 8-12; 1-3 months, level 6-9; and 3-6 months, level 5-8. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Family History of Diabetes | Number | participants |
|
| Body Mass Index | Mean | Standard Deviation | kg/m^2 |
|
| Systolic Blood Pressure | Mean | Standard Deviation | mmHg |
|
| Diastolic Blood Pressure | Mean | Standard Deviation | mmHg |
|
| Cholesterol Medications | Count of Participants | Participants |
|
| Cholestoral | Mean | Standard Deviation | mmol/L |
|
| Low-Density Lipoproteins | Mean | Standard Deviation | mmol/L |
|
| High-Density Lipoproteins | Mean | Standard Deviation | mmol/L |
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| Triglycerides | Mean | Standard Deviation | mmol/L |
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| Fasting Glucose | Mean | Standard Deviation | mmol/L |
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| Random Glucose | Mean | Standard Deviation | mmol/L |
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| Peak Panel-Reactive Antibody (PRA) before transplant | Panel reactive antibody (PRA) testing is performed on patients prior to transplantation in an effort to identify the potential presence of anti-HLA antibodies and minimize the risk of antibody mediated rejection. The inclusion criteria for this study was a peak PRA <30%. | Median | Full Range | % |
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| Donor Type | Number | participants |
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| Donor Age | Median | Inter-Quartile Range | years |
|
| Human Leukocyte Antigen (HLA) Matches | Human Leukocyte Antigen (HLA) testing is done before an organ transplant to find out if tissues match between the donor and the person receiving the transplant. | Count of Participants | Participants |
|
| OG001 | Standard Target Tacrolimus (Advagraf) | This group will receive basiliximab induction (40 mg total) with IV solumedrol, MPA (Mycophenolate Mofetil or Mycophenolate Sodium), and "standard target" Advagraf. Tacrolimus: Standard dose of tacrolimus Advagraf (0.25mg/kg) orally once daily dosed as per manufacturer's recommendation to target trough levels as per Table 1 Table 1 Months post tx 0-1 month; level 8-12; 1-3 months, level 6-9; and 3-6 months, level 5-8. |
|
|
| Secondary | Number of Participant Deaths | Death of any participant by end of study. | The discrepancy in the overall number of participants with outcome measure data and the overall number of participants in the participant flow module is seen because 28 participants in total have outcome measure data available. | Posted | Count of Participants | Participants | 6 months post transplant |
|
|
|
| Secondary | Number of Participants With Graft Failure | Any graft failure by the end of the study. | The discrepancy in the overall number of participants with outcome measure data and the overall number of participants in the participant flow module is seen because 28 participants in total have outcome measure data available. | Posted | Count of Participants | Participants | 6 months post transplant |
|
|
|
| Secondary | Number of Participants With Dialysis Events | Any dialysis required by end of study. | The discrepancy in the overall number of participants with outcome measure data and the overall number of participants in the participant flow module is seen because 28 participants in total have outcome measure data available. | Posted | Count of Participants | Participants | 6 months post transplant |
|
|
|
| Secondary | Number of Participants With Infection Events | Any infection (CMV, opportunistic infections including urinary tract infections requiring treatment, pneumonia) by end of study. | The discrepancy in the overall number of participants with outcome measure data and the overall number of participants in the participant flow module is seen because 28 participants in total have outcome measure data available. | Posted | Count of Participants | Participants | 6 months post transplant |
|
|
|
| Secondary | Number of Participants With Hospitalization Events | Any hospitalization by end of study. | The discrepancy in the overall number of participants with outcome measure data and the overall number of participants in the participant flow module is seen because 28 participants in total have outcome measure data available. | Posted | Count of Participants | Participants | 6 months post transplant |
|
|
|
| Secondary | Number of Participants With Malignancy Events | Any malignancy (including post-transplant lymphoproliferative disease) by end of study. | The discrepancy in the overall number of participants with outcome measure data and the overall number of participants in the participant flow module is seen because 28 participants in total have outcome measure data available. | Posted | Count of Participants | Participants | 6 months post transplant |
|
|
|
| Secondary | Number of Participants With Cardiovascular Event | Any cardiovascular events by end of study. | The discrepancy in the overall number of participants with outcome measure data and the overall number of participants in the participant flow module is seen because 28 participants in total have outcome measure data available. | Posted | Count of Participants | Participants | 6 months post transplant |
|
|
|
| Secondary | Number of Any Leukopenia Events | Any leukopenia by end of study. | The discrepancy in the overall number of participants with outcome measure data and the overall number of participants in the participant flow module is seen because 28 participants in total have outcome measure data available. | Posted | Number | events | 6 months post transplant |
|
|
|
| Secondary | Number of Leukopenia Events on ≥2 Occasions | Any leukopenia on ≥2 occasions by end of study. | The discrepancy in the overall number of participants with outcome measure data and the overall number of participants in the participant flow module is seen because 28 participants in total have outcome measure data available. | Posted | Number | events | 6 months post transplant |
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|
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| Secondary | Change From Baseline in Weight | Any changes in weight by end of study. | The discrepancy in the overall number of participants with outcome measure data and the overall number of participants in the participant flow module is seen because 28 participants in total have outcome measure data available. | Posted | Median | Inter-Quartile Range | kg | baseline to 6 months post transplant |
|
|
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| Secondary | eGFR at 6 Months | Participant eGFR value by end of study. | The discrepancy in the overall number of participants with outcome measure data and the overall number of participants in the participant flow module is seen because 28 participants in total have outcome measure data available. | Posted | Median | Inter-Quartile Range | mL/min/1.73^2 | 6 months post transplant |
|
|
|
| 0 |
| 14 |
| 7 |
| 14 |
| 0 |
| 14 |
| EG001 | Standard Target Tacrolimus (Advagraf) | This group will receive basiliximab induction (40 mg total) with IV solumedrol, MPA (Mycophenolate Mofetil or Mycophenolate Sodium), and "standard target" Advagraf. Tacrolimus: Standard dose of tacrolimus Advagraf (0.25mg/kg) orally once daily dosed as per manufacturer's recommendation to target trough levels as per Table 1 Table 1 Months post tx 0-1 month; level 8-12; 1-3 months, level 6-9; and 3-6 months, level 5-8. | 0 | 14 | 7 | 14 | 0 | 14 |
| Acute Rejection | Renal and urinary disorders | Non-systematic Assessment |
|
| Malignancy | Immune system disorders | Non-systematic Assessment |
|
| Infections | Infections and infestations | Non-systematic Assessment |
|
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