Graft Rejection, Kidney Failure
Conditions
Keywords
Heart Transplant, Kidney Failure
Brief summary
The primary purpose of this study is to determine whether converting from calcineurin inhibitor (CNI) therapy to sirolimus therapy will be more effective than continuing calcineurin inhibitor therapy with respect to renal function in cardiac transplant recipients with mild to moderate renal dysfunction.
Interventions
Cyclosporine and tacrolimus are provided by the sites and dosed to achieve a target trough level determined by the investigator; therefore, form, dosage, and frequency are site and patient specific. Duration should be 52 weeks on-therapy.
DRUGsirolimus
Oral (1 and 2 mg) tablets, dosing should be once daily to achieve a target trough level of 7- 15 ng/mL. Duration should be 52 weeks on-therapy.
Sponsors
Wyeth is now a wholly owned subsidiary of Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Cardiac transplant recipients age 18 years or older receiving cyclosporine or tacrolimus since the time of transplant. * 12 months after cardiac transplantation but less than 96 months post-transplantation.
Exclusion criteria
* Multiple-organ transplant recipients (such as heart-lung, heart-kidney, or heart after kidney transplant recipients). * Prior or current use of sirolimus or everolimus unless administration was part of a CNI holiday lasting no more than 10 days. * History of acute rejection within the last 3 months, malignancy within the last 5 years (except for adequately treated basal cell or squamous cell carcinoma of the skin), and human immunodeficiency virus (HIV) patients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 52 Weeks Post-randomization | Baseline and Week 52 | Creatinine Clearance (CC) calculated using Cockcroft-Gault equation, adjusted for body surface area. Calculated CC: method to approximate kidney function. It measures rate creatinine (substance formed from metabolism of creatine) is cleared from blood by kidneys. Normal adult creatinine clearance is greater than or equal to (≥) 90 milliliters per minute per 1.73 meters squared (mL/min/1.73m\^2). Change from baseline=CC at Week 52 minus CC at baseline where higher scores represented improved renal function; Least squares mean adjusted for baseline calculated creatinine clearance and center. |
| Calculated Creatinine Clearance (Cockcroft-Gault Equation) at Baseline | Baseline | Creatinine clearance at baseline calculated using Cockcroft-Gault equation and adjusted for body surface area. Calculated CC: method to approximate kidney function. It measures rate creatinine (substance formed from metabolism of creatine) is cleared from blood by kidneys. Normal adult creatinine clearance is ≥ 90 mL/min/1.73m\^2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at Baseline | Baseline | Creatinine clearance calculated using MDRD equation. Calculated CC: method to approximate kidney function. It measures rate creatinine (substance formed from metabolism of creatine) is cleared from blood by kidneys. Normal adult creatinine clearance is ≥ 90 mL/min/1.73m\^2. |
| Change From Baseline in Serum Creatinine Level at 4, 16, 24, 32, 40, and 52 Weeks Post-randomization | Baseline and Weeks 4, 16, 24, 32, 40, and 52 | Serum creatinine is an indicator of kidney function. Creatinine is a substance formed from the metabolism of creatine, commonly found in blood, urine, and muscle tissue. It is removed from the blood by the kidneys and excreted in urine. Normal adult blood levels of creatinine=45 to 90 micromoles per liter (mcmol/L) for females, 60 to 110 mcmol/L for males, however normal values are age-dependent. Change from baseline=creatinine level at Week x minus baseline level where higher scores represented decreased kidney function. Least squares mean adjusted for treatment group and center. |
| Serum Creatinine Level at Baseline | Baseline | Serum creatinine is an indicator of kidney function. Creatinine is a substance formed from the metabolism of creatine, commonly found in blood, urine, and muscle tissue. It is removed from the blood by the kidneys and excreted in urine. |
| Annual Change in Calculated Creatinine Clearance (Cockcroft-Gault Equation) | Baseline to discontinuation (up to Week 52) | The change in creatinine clearance over time assessed using the random coefficient slope of the regression line with creatinine clearance as the dependent variable and study day as the independent variable. Time points calculated as study days, relative to time of randomization of study medication. Observed data multiplied by a scale factor of 365 to express an annual change. |
| Overall Survival (OS) | Baseline until death (up to Week 56) | Survival time from the start of study treatment to date of death due to any cause, censored at the last visit if no death. Death was determined from the Death report. The distribution of time to death was to be estimated using Kaplan-Meier method and compared between treatment groups with a proportional hazard model. The number and percent of survival at 6 and 12 months were to be reported. |
| Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 4, 16, 24, 32, and 40 Weeks Post-randomization | Baseline and Weeks 4, 16, 24, 32, and 40 | Creatinine Clearance (CC) calculated using Cockcroft-Gault equation, adjusted for body surface area. Calculated CC: method to approximate kidney function. It measures rate creatinine (substance formed from metabolism of creatine) is cleared from blood by kidneys. Normal adult creatinine clearance is ≥ 90 mL/min/1.73m\^2. Change from baseline=CC at Week X minus CC at baseline where higher scores represented improved renal function; Least squares mean adjusted for baseline calculated creatinine clearance and center. |
| Number of Participants With Biopsy-confirmed Acute Rejection by Severity | Baseline to Week 52 | Severity of acute rejection summarized using revised 2005 ISHLT criteria. Grade 0R: no rejection, Grade 1R: Focal (perivascular or interstitial) infiltrate without necrosis, diffuse but sparse infiltrate without necrosis, or one focus only with aggressive infiltration and/or focal myocyte damage, Grade 2R:Multifocal aggressive infiltrates and/or myocyte damage, and Grade 3R:Diffuse inflammatory process with necrosis, or diffuse aggressive polymorphous with necrosis, increased infiltrate, changes in edema, hemorrhage and vasculitis. |
| Time to First Acute Rejection | Baseline to Week 52 | Time from baseline to first biopsy-confirmed acute rejection defined as any of the following (based on ISHLT 1990 criteria): all rejections Grade 3A or higher, any rejection accompanied by hemodynamic compromise, or any rejection requiring treatment. ISHLT Grade 3A or higher included: Multifocal aggressive infiltrates and/or myocyte damage, diffuse inflammatory process with necrosis, diffuse aggressive polymorphus with necrosis, increased infiltrates, and changes in edema, hemorrhage, or vasculitis. |
| Number of Participants Requiring Antibody Use in Treatment of Acute Rejection | Baseline to Week 52 | Number of participants requiring antilymphocyte antibody therapy with suspected or biopsy-proven, steroid-resistant, acute rejection with or without hemodynamic compromise. Acute rejection based on ISHLT 1990 criteria: all rejections Grade 3A or higher, any rejection accompanied by hemodynamic compromise, or any rejection requiring treatment. ISHLT Grade 3A or higher included: Multifocal aggressive infiltrates and/or myocyte damage, diffuse inflammatory process with necrosis, diffuse aggressive polymorphus with necrosis, increased infiltrates, and changes in edema, hemorrhage, or vasculitis. |
| Number of Participants in Sirolimus Treatment Group Requiring Conversion Back to CNI Therapy | Baseline up to Week 52 | — |
| Number of Participants With Acute Rejection | Baseline to Week 52 | Based on International Society for Heart and Lung Transplantation \[ISHLT\] 1990 criteria: rejections Grade 3A or higher, rejection accompanied by hemodynamic compromise or requiring treatment. Grade 3A or higher included: multifocal aggressive infiltrates and/or myocyte damage, diffuse inflammatory process with necrosis, diffuse aggressive polymorphus with necrosis, increased infiltrates, and changes in edema, hemorrhage, or vasculitis. Biopsies performed for clinically suspected rejection (for cause), site's standard of care (site protocol biopsy), or protocol mandated. |
| Change From Baseline in Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at 4, 16, 24, 32, 40 and 52 Weeks Post-randomization | Baseline and Weeks 4, 16, 24, 32, 40 and 52 | Creatinine clearance calculated using MDRD equation. Normal adult creatinine clearance is ≥ 90 mL/min/1.73m\^2. Change from baseline=CC at Week X minus CC at baseline where higher scores represented improved renal function. Least squares mean adjusted for baseline calculated creatinine clearance (MDRD) and center. |
Countries
Australia, Austria, Canada, New Zealand, Spain, Switzerland, United States
Participant flow
Recruitment details
Actual number of participants randomized was 121; however 5 participants randomized in error. They were withdrawn from study as screen failures, not administered study drug. Participants randomized (121) lower than planned (200); more sites added, time period to enroll extended twice up to 2.5 years. Despite this, final enrollment below planned.
Participants by arm
| Arm | Count |
|---|---|
| Cyclosporine or Tacrolimus Continuation of Calcineurin inhibitor (CNI) regimen; included cyclosporine (CsA) or tacrolimus (TAC) which were dosed to achieve a target trough level determined by investigator; therefore, form, dosage, and frequency were site and patient specific. CsA therapy could have been switched to TAC therapy and vice versa, as warranted by clinical circumstances. | 59 |
| Sirolimus (SRL) Conversion from CNI therapy to Sirolimus: Sirolimus initiated with oral tablets administered once daily (1 to 5 milligrams per day) to achieve target trough of 8-15 nanograms per milliliter (ng/mL). Protocol was later amended to allow target troughs of 7-15 ng/mL for duration of study. CNI discontinued within 8 weeks post randomization. | 57 |
| Total | 116 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 2 |
| Overall Study | Other | 1 | 0 |
| Overall Study | Physician Decision | 2 | 1 |
| Overall Study | Randomized, not treated | 2 | 0 |
| Overall Study | Withdrawal by Subject | 5 | 0 |
Baseline characteristics
| Characteristic | Cyclosporine or Tacrolimus | Sirolimus (SRL) | Total |
|---|---|---|---|
| Age Continuous | 58.93 years STANDARD_DEVIATION 8.01 | 57.40 years STANDARD_DEVIATION 9.42 | 58.18 years STANDARD_DEVIATION 8.73 |
| Sex: Female, Male Female | 5 Participants | 12 Participants | 17 Participants |
| Sex: Female, Male Male | 54 Participants | 45 Participants | 99 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 40 / 57 | 54 / 57 |
| serious Total, serious adverse events | 13 / 57 | 30 / 57 |
Outcome results
Primary
Calculated Creatinine Clearance (Cockcroft-Gault Equation) at Baseline
Creatinine clearance at baseline calculated using Cockcroft-Gault equation and adjusted for body surface area. Calculated CC: method to approximate kidney function. It measures rate creatinine (substance formed from metabolism of creatine) is cleared from blood by kidneys. Normal adult creatinine clearance is ≥ 90 mL/min/1.73m\^2.
Time frame: Baseline
Population: ITT; N=participants with all measurements required for calculated creatinine clearance.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cyclosporine or Tacrolimus | Calculated Creatinine Clearance (Cockcroft-Gault Equation) at Baseline | 57.09 mL/min/1.73m^2 | Standard Deviation 11.96 |
| Sirolimus (SRL) | Calculated Creatinine Clearance (Cockcroft-Gault Equation) at Baseline | 57.75 mL/min/1.73m^2 | Standard Deviation 14.04 |
Primary
Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 52 Weeks Post-randomization
Creatinine Clearance (CC) calculated using Cockcroft-Gault equation, adjusted for body surface area. Calculated CC: method to approximate kidney function. It measures rate creatinine (substance formed from metabolism of creatine) is cleared from blood by kidneys. Normal adult creatinine clearance is greater than or equal to (≥) 90 milliliters per minute per 1.73 meters squared (mL/min/1.73m\^2). Change from baseline=CC at Week 52 minus CC at baseline where higher scores represented improved renal function; Least squares mean adjusted for baseline calculated creatinine clearance and center.
Time frame: Baseline and Week 52
Population: Intent-to-Treat (ITT) Population: all randomized participants; all available data (on-therapy and off-therapy) included; Last observation carried forward (LOCF) for data missing due to skipped visits or participant withdrawal from study. Number of participants analyzed (N)=those with all measurements required for calculated creatinine clearance.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Cyclosporine or Tacrolimus | Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 52 Weeks Post-randomization | -1.35 mL/min/1.73m^2 | Standard Error 1.18 |
| Sirolimus (SRL) | Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 52 Weeks Post-randomization | 3.03 mL/min/1.73m^2 | Standard Error 1.29 |
Comparison: Change from baseline to Week 52p-value: 0.004ANCOVA
Secondary
Annual Change in Calculated Creatinine Clearance (Cockcroft-Gault Equation)
The change in creatinine clearance over time assessed using the random coefficient slope of the regression line with creatinine clearance as the dependent variable and study day as the independent variable. Time points calculated as study days, relative to time of randomization of study medication. Observed data multiplied by a scale factor of 365 to express an annual change.
Time frame: Baseline to discontinuation (up to Week 52)
Population: ITT; N=participants with all measurements required for calculated creatinine clearance. All observed data up to the point of discontinuation of the study were used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cyclosporine or Tacrolimus | Annual Change in Calculated Creatinine Clearance (Cockcroft-Gault Equation) | -0.740 mL/min/1.73m^2 |
| Sirolimus (SRL) | Annual Change in Calculated Creatinine Clearance (Cockcroft-Gault Equation) | 1.571 mL/min/1.73m^2 |
p-value: 0.12695% CI: [-5.282, 0.66]Random coefficient model
Secondary
Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at Baseline
Creatinine clearance calculated using MDRD equation. Calculated CC: method to approximate kidney function. It measures rate creatinine (substance formed from metabolism of creatine) is cleared from blood by kidneys. Normal adult creatinine clearance is ≥ 90 mL/min/1.73m\^2.
Time frame: Baseline
Population: ITT.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cyclosporine or Tacrolimus | Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at Baseline | 55.39 mL/min/1.73m^2 | Standard Deviation 12.84 |
| Sirolimus (SRL) | Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at Baseline | 54.47 mL/min/1.73m^2 | Standard Deviation 14.14 |
Secondary
Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 4, 16, 24, 32, and 40 Weeks Post-randomization
Creatinine Clearance (CC) calculated using Cockcroft-Gault equation, adjusted for body surface area. Calculated CC: method to approximate kidney function. It measures rate creatinine (substance formed from metabolism of creatine) is cleared from blood by kidneys. Normal adult creatinine clearance is ≥ 90 mL/min/1.73m\^2. Change from baseline=CC at Week X minus CC at baseline where higher scores represented improved renal function; Least squares mean adjusted for baseline calculated creatinine clearance and center.
Time frame: Baseline and Weeks 4, 16, 24, 32, and 40
Population: ITT; All available data (on-therapy and off-therapy) were included; LOCF for data points missing due to skipped visits or participant withdrawal from study; N=participants with all measurements required for calculated creatinine clearance.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Cyclosporine or Tacrolimus | Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 4, 16, 24, 32, and 40 Weeks Post-randomization | Week 16 | -2.16 mL/min/1.73m^2 | Standard Error 1.37 |
| Cyclosporine or Tacrolimus | Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 4, 16, 24, 32, and 40 Weeks Post-randomization | Week 32 | -0.76 mL/min/1.73m^2 | Standard Error 1.32 |
| Cyclosporine or Tacrolimus | Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 4, 16, 24, 32, and 40 Weeks Post-randomization | Week 24 | -1.91 mL/min/1.73m^2 | Standard Error 1.28 |
| Cyclosporine or Tacrolimus | Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 4, 16, 24, 32, and 40 Weeks Post-randomization | Week 40 | 0.34 mL/min/1.73m^2 | Standard Error 1.39 |
| Cyclosporine or Tacrolimus | Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 4, 16, 24, 32, and 40 Weeks Post-randomization | Week 4 | -0.20 mL/min/1.73m^2 | Standard Error 1.06 |
| Sirolimus (SRL) | Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 4, 16, 24, 32, and 40 Weeks Post-randomization | Week 40 | 2.70 mL/min/1.73m^2 | Standard Error 1.52 |
| Sirolimus (SRL) | Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 4, 16, 24, 32, and 40 Weeks Post-randomization | Week 4 | 2.96 mL/min/1.73m^2 | Standard Error 1.16 |
| Sirolimus (SRL) | Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 4, 16, 24, 32, and 40 Weeks Post-randomization | Week 16 | 3.79 mL/min/1.73m^2 | Standard Error 1.5 |
| Sirolimus (SRL) | Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 4, 16, 24, 32, and 40 Weeks Post-randomization | Week 24 | 2.15 mL/min/1.73m^2 | Standard Error 1.4 |
| Sirolimus (SRL) | Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at 4, 16, 24, 32, and 40 Weeks Post-randomization | Week 32 | 2.22 mL/min/1.73m^2 | Standard Error 1.45 |
Comparison: Change from baseline to Week 4p-value: 0.018ANCOVA
Comparison: Change from baseline to Week 16p-value: <0.001ANCOVA
Comparison: Change from baseline to Week 24p-value: 0.012ANCOVA
Comparison: Change from baseline to Week 32p-value: 0.072ANCOVA
Comparison: Change from baseline to Week 40p-value: 0.175ANCOVA
Secondary
Change From Baseline in Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at 4, 16, 24, 32, 40 and 52 Weeks Post-randomization
Creatinine clearance calculated using MDRD equation. Normal adult creatinine clearance is ≥ 90 mL/min/1.73m\^2. Change from baseline=CC at Week X minus CC at baseline where higher scores represented improved renal function. Least squares mean adjusted for baseline calculated creatinine clearance (MDRD) and center.
Time frame: Baseline and Weeks 4, 16, 24, 32, 40 and 52
Population: ITT; All available data (on-therapy and off-therapy) were included; LOCF for data points missing due to skipped visits or participant withdrawal from study.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Cyclosporine or Tacrolimus | Change From Baseline in Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at 4, 16, 24, 32, 40 and 52 Weeks Post-randomization | Week 16 | -1.92 mL/min/1.73m^2 | Standard Error 1.4 |
| Cyclosporine or Tacrolimus | Change From Baseline in Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at 4, 16, 24, 32, 40 and 52 Weeks Post-randomization | Week 24 | -1.47 mL/min/1.73m^2 | Standard Error 1.36 |
| Cyclosporine or Tacrolimus | Change From Baseline in Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at 4, 16, 24, 32, 40 and 52 Weeks Post-randomization | Week 40 | 0.69 mL/min/1.73m^2 | Standard Error 1.52 |
| Cyclosporine or Tacrolimus | Change From Baseline in Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at 4, 16, 24, 32, 40 and 52 Weeks Post-randomization | Week 4 | -0.00 mL/min/1.73m^2 | Standard Error 1.16 |
| Cyclosporine or Tacrolimus | Change From Baseline in Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at 4, 16, 24, 32, 40 and 52 Weeks Post-randomization | Week 52 | -0.90 mL/min/1.73m^2 | Standard Error 1.26 |
| Cyclosporine or Tacrolimus | Change From Baseline in Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at 4, 16, 24, 32, 40 and 52 Weeks Post-randomization | Week 32 | -0.15 mL/min/1.73m^2 | Standard Error 1.43 |
| Sirolimus (SRL) | Change From Baseline in Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at 4, 16, 24, 32, 40 and 52 Weeks Post-randomization | Week 52 | 3.26 mL/min/1.73m^2 | Standard Error 1.36 |
| Sirolimus (SRL) | Change From Baseline in Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at 4, 16, 24, 32, 40 and 52 Weeks Post-randomization | Week 24 | 2.54 mL/min/1.73m^2 | Standard Error 1.47 |
| Sirolimus (SRL) | Change From Baseline in Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at 4, 16, 24, 32, 40 and 52 Weeks Post-randomization | Week 32 | 2.44 mL/min/1.73m^2 | Standard Error 1.54 |
| Sirolimus (SRL) | Change From Baseline in Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at 4, 16, 24, 32, 40 and 52 Weeks Post-randomization | Week 4 | 3.18 mL/min/1.73m^2 | Standard Error 1.25 |
| Sirolimus (SRL) | Change From Baseline in Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at 4, 16, 24, 32, 40 and 52 Weeks Post-randomization | Week 40 | 2.69 mL/min/1.73m^2 | Standard Error 1.64 |
| Sirolimus (SRL) | Change From Baseline in Calculated Creatinine Clearance (Modification of Diet in Renal Disease [MDRD] Equation) at 4, 16, 24, 32, 40 and 52 Weeks Post-randomization | Week 16 | 4.30 mL/min/1.73m^2 | Standard Error 1.51 |
Comparison: Change from baseline to Week 4p-value: 0.031ANCOVA
Comparison: Change from baseline to Week 16p-value: <0.001ANCOVA
Comparison: Change from baseline to Week 24p-value: 0.02ANCOVA
Comparison: Change from baseline to Week 32p-value: 0.151ANCOVA
Comparison: Change from baseline to Week 40p-value: 0.295ANCOVA
Comparison: Change from baseline to Week 52p-value: 0.01ANCOVA
Secondary
Change From Baseline in Serum Creatinine Level at 4, 16, 24, 32, 40, and 52 Weeks Post-randomization
Serum creatinine is an indicator of kidney function. Creatinine is a substance formed from the metabolism of creatine, commonly found in blood, urine, and muscle tissue. It is removed from the blood by the kidneys and excreted in urine. Normal adult blood levels of creatinine=45 to 90 micromoles per liter (mcmol/L) for females, 60 to 110 mcmol/L for males, however normal values are age-dependent. Change from baseline=creatinine level at Week x minus baseline level where higher scores represented decreased kidney function. Least squares mean adjusted for treatment group and center.
Time frame: Baseline and Weeks 4, 16, 24, 32, 40, and 52
Population: ITT, All available data (on-therapy and off-therapy) were included; LOCF for data points missing due to skipped visits or participant withdrawal from study.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Cyclosporine or Tacrolimus | Change From Baseline in Serum Creatinine Level at 4, 16, 24, 32, 40, and 52 Weeks Post-randomization | Week 24 | 8.02 mcmol/L | Standard Error 2.21 |
| Cyclosporine or Tacrolimus | Change From Baseline in Serum Creatinine Level at 4, 16, 24, 32, 40, and 52 Weeks Post-randomization | Week 4 | 1.68 mcmol/L | Standard Error 2 |
| Cyclosporine or Tacrolimus | Change From Baseline in Serum Creatinine Level at 4, 16, 24, 32, 40, and 52 Weeks Post-randomization | Week 16 | 7.96 mcmol/L | Standard Error 2.62 |
| Cyclosporine or Tacrolimus | Change From Baseline in Serum Creatinine Level at 4, 16, 24, 32, 40, and 52 Weeks Post-randomization | Week 32 | 4.08 mcmol/L | Standard Error 2.52 |
| Cyclosporine or Tacrolimus | Change From Baseline in Serum Creatinine Level at 4, 16, 24, 32, 40, and 52 Weeks Post-randomization | Week 40 | 2.44 mcmol/L | Standard Error 2.7 |
| Cyclosporine or Tacrolimus | Change From Baseline in Serum Creatinine Level at 4, 16, 24, 32, 40, and 52 Weeks Post-randomization | Week 52 | 4.76 mcmol/L | Standard Error 2.22 |
| Sirolimus (SRL) | Change From Baseline in Serum Creatinine Level at 4, 16, 24, 32, 40, and 52 Weeks Post-randomization | Week 40 | 2.81 mcmol/L | Standard Error 2.9 |
| Sirolimus (SRL) | Change From Baseline in Serum Creatinine Level at 4, 16, 24, 32, 40, and 52 Weeks Post-randomization | Week 32 | -2.80 mcmol/L | Standard Error 2.71 |
| Sirolimus (SRL) | Change From Baseline in Serum Creatinine Level at 4, 16, 24, 32, 40, and 52 Weeks Post-randomization | Week 4 | -4.95 mcmol/L | Standard Error 2.15 |
| Sirolimus (SRL) | Change From Baseline in Serum Creatinine Level at 4, 16, 24, 32, 40, and 52 Weeks Post-randomization | Week 52 | -4.39 mcmol/L | Standard Error 2.39 |
| Sirolimus (SRL) | Change From Baseline in Serum Creatinine Level at 4, 16, 24, 32, 40, and 52 Weeks Post-randomization | Week 16 | -5.52 mcmol/L | Standard Error 2.82 |
| Sirolimus (SRL) | Change From Baseline in Serum Creatinine Level at 4, 16, 24, 32, 40, and 52 Weeks Post-randomization | Week 24 | -0.89 mcmol/L | Standard Error 2.37 |
Comparison: Change from baseline to Week 4p-value: 0.009ANCOVA
Comparison: Change from baseline to Week 16p-value: <0.001ANCOVA
Comparison: Change from baseline to Week 24p-value: 0.002ANCOVA
Comparison: Change from baseline to Week 32p-value: 0.03ANCOVA
Comparison: Change from baseline to Week 40p-value: 0.121ANCOVA
Comparison: Change from baseline to Week 52p-value: 0.001ANCOVA
Secondary
Number of Participants in Sirolimus Treatment Group Requiring Conversion Back to CNI Therapy
Time frame: Baseline up to Week 52
Population: Safety population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cyclosporine or Tacrolimus | Number of Participants in Sirolimus Treatment Group Requiring Conversion Back to CNI Therapy | 21 Participants |
Secondary
Number of Participants Requiring Antibody Use in Treatment of Acute Rejection
Number of participants requiring antilymphocyte antibody therapy with suspected or biopsy-proven, steroid-resistant, acute rejection with or without hemodynamic compromise. Acute rejection based on ISHLT 1990 criteria: all rejections Grade 3A or higher, any rejection accompanied by hemodynamic compromise, or any rejection requiring treatment. ISHLT Grade 3A or higher included: Multifocal aggressive infiltrates and/or myocyte damage, diffuse inflammatory process with necrosis, diffuse aggressive polymorphus with necrosis, increased infiltrates, and changes in edema, hemorrhage, or vasculitis.
Time frame: Baseline to Week 52
Population: Safety population; N=participants who had biopsy-confirmed acute rejection.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cyclosporine or Tacrolimus | Number of Participants Requiring Antibody Use in Treatment of Acute Rejection | 1 Participants |
| Sirolimus (SRL) | Number of Participants Requiring Antibody Use in Treatment of Acute Rejection | 0 Participants |
Secondary
Number of Participants With Acute Rejection
Based on International Society for Heart and Lung Transplantation \[ISHLT\] 1990 criteria: rejections Grade 3A or higher, rejection accompanied by hemodynamic compromise or requiring treatment. Grade 3A or higher included: multifocal aggressive infiltrates and/or myocyte damage, diffuse inflammatory process with necrosis, diffuse aggressive polymorphus with necrosis, increased infiltrates, and changes in edema, hemorrhage, or vasculitis. Biopsies performed for clinically suspected rejection (for cause), site's standard of care (site protocol biopsy), or protocol mandated.
Time frame: Baseline to Week 52
Population: Safety population; n=number of participants analyzed for the specified type of biopsy.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cyclosporine or Tacrolimus | Number of Participants With Acute Rejection | Standard of Care biopsies (n=11, 11) | 0 Participants |
| Cyclosporine or Tacrolimus | Number of Participants With Acute Rejection | For cause biopsies (n=57, 57) | 1 Participants |
| Cyclosporine or Tacrolimus | Number of Participants With Acute Rejection | Protocol mandated biopsies (n=0, 39) | NA Participants |
| Sirolimus (SRL) | Number of Participants With Acute Rejection | Standard of Care biopsies (n=11, 11) | 2 Participants |
| Sirolimus (SRL) | Number of Participants With Acute Rejection | For cause biopsies (n=57, 57) | 5 Participants |
| Sirolimus (SRL) | Number of Participants With Acute Rejection | Protocol mandated biopsies (n=0, 39) | 7 Participants |
Comparison: For-cause Biopsy-Confirmed Acute Rejection compared between treatment groupsp-value: 0.206Fisher Exact
Comparison: Standard of Care Biopsy-Confirmed Acute Rejection compared between treatment groupsp-value: 0.476Fisher Exact
Secondary
Number of Participants With Biopsy-confirmed Acute Rejection by Severity
Severity of acute rejection summarized using revised 2005 ISHLT criteria. Grade 0R: no rejection, Grade 1R: Focal (perivascular or interstitial) infiltrate without necrosis, diffuse but sparse infiltrate without necrosis, or one focus only with aggressive infiltration and/or focal myocyte damage, Grade 2R:Multifocal aggressive infiltrates and/or myocyte damage, and Grade 3R:Diffuse inflammatory process with necrosis, or diffuse aggressive polymorphous with necrosis, increased infiltrate, changes in edema, hemorrhage and vasculitis.
Time frame: Baseline to Week 52
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cyclosporine or Tacrolimus | Number of Participants With Biopsy-confirmed Acute Rejection by Severity | Grade 2R site protocol | 0 Participants |
| Cyclosporine or Tacrolimus | Number of Participants With Biopsy-confirmed Acute Rejection by Severity | Grade 1R for cause | 0 Participants |
| Cyclosporine or Tacrolimus | Number of Participants With Biopsy-confirmed Acute Rejection by Severity | Grade 2R for cause | 0 Participants |
| Cyclosporine or Tacrolimus | Number of Participants With Biopsy-confirmed Acute Rejection by Severity | Grade 1R site protocol | 0 Participants |
| Cyclosporine or Tacrolimus | Number of Participants With Biopsy-confirmed Acute Rejection by Severity | Grade 2R protocol mandated | NA Participants |
| Cyclosporine or Tacrolimus | Number of Participants With Biopsy-confirmed Acute Rejection by Severity | Grade 3R protocol mandated | NA Participants |
| Cyclosporine or Tacrolimus | Number of Participants With Biopsy-confirmed Acute Rejection by Severity | Grade 3R for cause | 1 Participants |
| Cyclosporine or Tacrolimus | Number of Participants With Biopsy-confirmed Acute Rejection by Severity | Grade 1R protocol mandated | NA Participants |
| Cyclosporine or Tacrolimus | Number of Participants With Biopsy-confirmed Acute Rejection by Severity | Grade 3R site protocol | 0 Participants |
| Cyclosporine or Tacrolimus | Number of Participants With Biopsy-confirmed Acute Rejection by Severity | Grade 0R site protocol | 0 Participants |
| Cyclosporine or Tacrolimus | Number of Participants With Biopsy-confirmed Acute Rejection by Severity | Grade 0R protocol mandated | NA Participants |
| Cyclosporine or Tacrolimus | Number of Participants With Biopsy-confirmed Acute Rejection by Severity | Grade 0R for cause | 0 Participants |
| Sirolimus (SRL) | Number of Participants With Biopsy-confirmed Acute Rejection by Severity | Grade 0R protocol mandated | 0 Participants |
| Sirolimus (SRL) | Number of Participants With Biopsy-confirmed Acute Rejection by Severity | Grade 1R protocol mandated | 0 Participants |
| Sirolimus (SRL) | Number of Participants With Biopsy-confirmed Acute Rejection by Severity | Grade 1R site protocol | 0 Participants |
| Sirolimus (SRL) | Number of Participants With Biopsy-confirmed Acute Rejection by Severity | Grade 2R protocol mandated | 6 Participants |
| Sirolimus (SRL) | Number of Participants With Biopsy-confirmed Acute Rejection by Severity | Grade 2R for cause | 4 Participants |
| Sirolimus (SRL) | Number of Participants With Biopsy-confirmed Acute Rejection by Severity | Grade 2R site protocol | 1 Participants |
| Sirolimus (SRL) | Number of Participants With Biopsy-confirmed Acute Rejection by Severity | Grade 0R for cause | 0 Participants |
| Sirolimus (SRL) | Number of Participants With Biopsy-confirmed Acute Rejection by Severity | Grade 0R site protocol | 0 Participants |
| Sirolimus (SRL) | Number of Participants With Biopsy-confirmed Acute Rejection by Severity | Grade 1R for cause | 0 Participants |
| Sirolimus (SRL) | Number of Participants With Biopsy-confirmed Acute Rejection by Severity | Grade 3R protocol mandated | 1 Participants |
| Sirolimus (SRL) | Number of Participants With Biopsy-confirmed Acute Rejection by Severity | Grade 3R for cause | 1 Participants |
| Sirolimus (SRL) | Number of Participants With Biopsy-confirmed Acute Rejection by Severity | Grade 3R site protocol | 1 Participants |
Secondary
Overall Survival (OS)
Survival time from the start of study treatment to date of death due to any cause, censored at the last visit if no death. Death was determined from the Death report. The distribution of time to death was to be estimated using Kaplan-Meier method and compared between treatment groups with a proportional hazard model. The number and percent of survival at 6 and 12 months were to be reported.
Time frame: Baseline until death (up to Week 56)
Population: Safety population: all randomized participants who received at least 1 dose of study medication; not analyzed by Kaplan-Meier because number of events limited to 2 deaths in the sirolimus group.
Secondary
Serum Creatinine Level at Baseline
Serum creatinine is an indicator of kidney function. Creatinine is a substance formed from the metabolism of creatine, commonly found in blood, urine, and muscle tissue. It is removed from the blood by the kidneys and excreted in urine.
Time frame: Baseline
Population: ITT.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cyclosporine or Tacrolimus | Serum Creatinine Level at Baseline | 125.42 mcmol/L | Standard Deviation 23.15 |
| Sirolimus (SRL) | Serum Creatinine Level at Baseline | 126.21 mcmol/L | Standard Deviation 29.63 |
Secondary
Time to First Acute Rejection
Time from baseline to first biopsy-confirmed acute rejection defined as any of the following (based on ISHLT 1990 criteria): all rejections Grade 3A or higher, any rejection accompanied by hemodynamic compromise, or any rejection requiring treatment. ISHLT Grade 3A or higher included: Multifocal aggressive infiltrates and/or myocyte damage, diffuse inflammatory process with necrosis, diffuse aggressive polymorphus with necrosis, increased infiltrates, and changes in edema, hemorrhage, or vasculitis.
Time frame: Baseline to Week 52
Population: Safety population; not analyzed because actual start date of rejection was unknown for those diagnosed by site protocol (SOC) biopsy and protocol-required biopsy.