Heart Transplantation
Conditions
Keywords
Heart Transplantation, Cardiac Transplantation, CNI-sparing, renal function, CNI, Cyclosporine A, Everolimus, mycophenolic acid
Brief summary
This study will assess whether a calcineurin inhibitor (CNI)-free regimen with everolimus and mycophenolic acid is associated with a better renal outcome as compared to the standard regimen containing cyclosporine A (which belongs to the class of CNIs) and everolimus; while both treatments are expected to be comparable with respect to efficacy.
Detailed description
This study will assess whether a calcineurin inhibitor (CNI)-free regimen with everolimus and mycophenolic acid is associated with a better renal outcome as compared to the standard regimen containing cyclosporine A (which belongs to the class of CNIs) and everolimus; while both treatments are expected to be comparable with respect to efficacy.
Interventions
DRUGEverolimus (EVR)
Everolimus 0.25mg, 0.75mg or 1.0mg based on blood levels (5-10 ng/mL)
DRUGcyclosporine A (CyA)
10 mg, 25 mg, 50 mg or 100 mg capsule according to blood levels for CNI-regimen group. For CNI-free-regimen dispense on month 6 to 9 only
DRUGtacrolimus (TAC)
0.5 mg, 1 mg, or 5 mg capsule given according to blood levels for CNI-regimen. For CNI-free-regimen give on month 6 to 9 only
180 mg or 360 mg tablet dosed 1440-2280 mg per day
DRUGmycophenolate mofetil (MMF)
250 mg or 500 mg tablets with a dose of 1500-3000 mg per day
DRUGCorticosteroids
according to local standard: 0.05-0.3 mg/kg of prednisolone or equivalent
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Heart transplantation, 3 months prior to enrollment * Patients have to receive an immunosuppressive regimen with Sandimmun® Optoral, Certican® and corticosteroids * Sufficient graft function * Sufficient renal function * Females capable of becoming pregnant must have a negative serum pregnancy test within 7 days prior to or at baseline, and are required to practice an approved method of birth control for the duration of the study and for a period of 6 weeks following discontinuation of study medication, even where there has been a history of infertility
Exclusion criteria
* Multi-organ recipients, re-transplantation, or previous transplant with any other organ. * Patients who are recipients of A-B-O incompatible transplants * Cold ischemia time \>6 hours * Historical or current peak PRA of \> 25% at time of transplantation * Already existing antibodies against the HLA-type of the receiving transplant Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Calculated Glomerular Filtration Rate (cGFR) Using Modification of Diet in Renal Disease (MDRD) Formula at Month 18 | Month 18 | Calculated Glomerular Filtration Rate (cGFR) Using Modification of Diet in Renal Disease (MDRD) Formula at Month 18 cGFR (in mL/min/1.73 m2) = 186.3\*(C-1.154)\*(A-0.203)\*G\*R where C = the serum concentration of creatinine (mg/dL), A = age (years), G = 0.742 when gender is female, otherwise G = 1, R = 1.21 when race is black, otherwise R = 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serum Creatinine at Month 6, 8, 9, 10 12 and 18 | Month 6, 8, 9, 10 12 and 18 | Serum Creatinine is an indicator of renal function measured in the blood |
| Reciprocal Creatinine Slope Between Month 6 and Month 18 | Between Month 6 and Month 18 | Reciprocal Creatinine Slope is an indication of renal function over time with a higher slope value indicating an improvement in renal function. |
| Calculated Glomerular Filtration Rate (cGFR) According to Cockcroft-Gault at Month 12 and 18 | Month 12 and 18 | Calculated Glomerular Filtration Rate (cGFR) according to Cockcroft-Gault at Month 12 and 18. For men: GFR=(140-Age) x Body weight (kg) / 72 x Serum Creatinine (mg/dl) For women: GFR=0.85 (140 -Age) x Body weight(kg)/ 72 x Serum Creatinine (mg/dl) |
| Occurrence of Treatment Failures From Month 6 to 9 and Month 9 to 18 | Month 6 to Month 9; Month 9 to Month 18 | Treatment failure was defined as composite endpoint of biopsy proven acute rejection of ISHLT 1990 grade ≥ 3A resp. ISHLT 2004 grade ≥ 2R, acute rejection episodes associated with hemodynamic compromise, graft loss / re-transplant, death, loss to follow up (at least one condition must be present). If participant had an occurrence in each period it was counted for each period. |
| Occurrence of Major Cardiac Events (MACE) From Month 6 to 18 | Month 6 to Month 18 | Major cardiac events (MACE) was defined as one of the following: any death, myocardial infarction, coronary artery bypass grafting |
Countries
Germany
Participant flow
Recruitment details
232 patients were screened, of these , 193 patients were included in safety set which included 31 non-randomized and 162 randomized. Of these, 145 patients were treated with study medication and had at least 1 post-baseline assessment of the primary outcome variable and included in the Full Analysis Set FAS.
Participants by arm
| Arm | Count |
|---|---|
| CNI-regimen CNI-regimen: cyclosporine A (CyA) or tacrolimus (TAC) with everolimus (EVR) with corticosteroids | 74 |
| CNI-free-regimen CNI-free regimen: everolimus (EVR) with MPA (either MMF or enteric coated mycophenolate sodium (EC-MPS)) and corticosteroids | 71 |
| Total | 145 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative problems | 0 | 1 |
| Overall Study | Adverse Event | 6 | 3 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Patient withdrew consent | 2 | 1 |
| Overall Study | Protocol Violation | 0 | 1 |
Baseline characteristics
| Characteristic | CNI-free-regimen | Total | CNI-regimen |
|---|---|---|---|
| Age, Continuous | 50.3 years STANDARD_DEVIATION 9.8 | 51.5 years STANDARD_DEVIATION 9.8 | 52.7 years STANDARD_DEVIATION 9.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 71 Participants | 145 Participants | 74 Participants |
| Sex: Female, Male Female | 12 Participants | 21 Participants | 9 Participants |
| Sex: Female, Male Male | 59 Participants | 124 Participants | 65 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 84 | 1 / 78 |
| other Total, other adverse events | 74 / 84 | 65 / 78 |
| serious Total, serious adverse events | 40 / 84 | 29 / 78 |
Outcome results
Primary
Calculated Glomerular Filtration Rate (cGFR) Using Modification of Diet in Renal Disease (MDRD) Formula at Month 18
Calculated Glomerular Filtration Rate (cGFR) Using Modification of Diet in Renal Disease (MDRD) Formula at Month 18 cGFR (in mL/min/1.73 m2) = 186.3\*(C-1.154)\*(A-0.203)\*G\*R where C = the serum concentration of creatinine (mg/dL), A = age (years), G = 0.742 when gender is female, otherwise G = 1, R = 1.21 when race is black, otherwise R = 1.
Time frame: Month 18
Population: Full Analysis Set-Last observation carried forward (FAS-LOCF)- 145 patients were treated with study medication and had at least 1 post-baseline assessment of the primary outcome variable but for this analysis only participants that had values at Month 18 were analyzed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CNI-regimen | Calculated Glomerular Filtration Rate (cGFR) Using Modification of Diet in Renal Disease (MDRD) Formula at Month 18 | 54.2 mL/min | Standard Deviation 17.9 |
| CNI-free-regimen | Calculated Glomerular Filtration Rate (cGFR) Using Modification of Diet in Renal Disease (MDRD) Formula at Month 18 | 66.9 mL/min | Standard Deviation 23 |
p-value: <0.000195% CI: [-16.5, -6.1]ANCOVA
Secondary
Calculated Glomerular Filtration Rate (cGFR) According to Cockcroft-Gault at Month 12 and 18
Calculated Glomerular Filtration Rate (cGFR) according to Cockcroft-Gault at Month 12 and 18. For men: GFR=(140-Age) x Body weight (kg) / 72 x Serum Creatinine (mg/dl) For women: GFR=0.85 (140 -Age) x Body weight(kg)/ 72 x Serum Creatinine (mg/dl)
Time frame: Month 12 and 18
Population: Full Analysis Set-Last observation carried forward (FAS-LOCF)- 145 patients were treated with study medication and had at least 1 post-baseline assessment of the primary outcome variable but for this analysis only participants that had values at Month 12 \& 18 were analyzed
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CNI-regimen | Calculated Glomerular Filtration Rate (cGFR) According to Cockcroft-Gault at Month 12 and 18 | Month 12 | 54.2 mL/min | Standard Deviation 19.7 |
| CNI-regimen | Calculated Glomerular Filtration Rate (cGFR) According to Cockcroft-Gault at Month 12 and 18 | Month 18 | 54.2 mL/min | Standard Deviation 17.9 |
| CNI-free-regimen | Calculated Glomerular Filtration Rate (cGFR) According to Cockcroft-Gault at Month 12 and 18 | Month 12 | 69.8 mL/min | Standard Deviation 23.4 |
| CNI-free-regimen | Calculated Glomerular Filtration Rate (cGFR) According to Cockcroft-Gault at Month 12 and 18 | Month 18 | 66.9 mL/min | Standard Deviation 23 |
Comparison: Month 12p-value: <0.000195% CI: [-19.6, -8.3]ANCOVA
Comparison: Month 18p-value: <0.000195% CI: [-16.5, -6.1]ANCOVA
Secondary
Occurrence of Major Cardiac Events (MACE) From Month 6 to 18
Major cardiac events (MACE) was defined as one of the following: any death, myocardial infarction, coronary artery bypass grafting
Time frame: Month 6 to Month 18
Population: Full Analysis Set FAS- 145 patients were treated with study medication and had at least 1 post-baseline assessment of the primary outcome variable
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CNI-regimen | Occurrence of Major Cardiac Events (MACE) From Month 6 to 18 | Myocardial infarction | 1 Occurences |
| CNI-regimen | Occurrence of Major Cardiac Events (MACE) From Month 6 to 18 | Death | 0 Occurences |
| CNI-free-regimen | Occurrence of Major Cardiac Events (MACE) From Month 6 to 18 | Myocardial infarction | 0 Occurences |
| CNI-free-regimen | Occurrence of Major Cardiac Events (MACE) From Month 6 to 18 | Death | 1 Occurences |
Secondary
Occurrence of Treatment Failures From Month 6 to 9 and Month 9 to 18
Treatment failure was defined as composite endpoint of biopsy proven acute rejection of ISHLT 1990 grade ≥ 3A resp. ISHLT 2004 grade ≥ 2R, acute rejection episodes associated with hemodynamic compromise, graft loss / re-transplant, death, loss to follow up (at least one condition must be present). If participant had an occurrence in each period it was counted for each period.
Time frame: Month 6 to Month 9; Month 9 to Month 18
Population: Full Analysis Set FAS- 145 patients were treated with study medication and had at least 1 post-baseline assessment of the primary outcome variable
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CNI-regimen | Occurrence of Treatment Failures From Month 6 to 9 and Month 9 to 18 | Month 6 to Month 9 Treatment failure - all reasons | 1 Occurences |
| CNI-regimen | Occurrence of Treatment Failures From Month 6 to 9 and Month 9 to 18 | Month 9 to Month 18 Treatment failure-all reasons | 3 Occurences |
| CNI-free-regimen | Occurrence of Treatment Failures From Month 6 to 9 and Month 9 to 18 | Month 6 to Month 9 Treatment failure - all reasons | 4 Occurences |
| CNI-free-regimen | Occurrence of Treatment Failures From Month 6 to 9 and Month 9 to 18 | Month 9 to Month 18 Treatment failure-all reasons | 15 Occurences |
Comparison: Month 6 to Month 9p-value: 0.203Fisher Exact
Comparison: Month 9 to Month 18p-value: 0.002Fisher Exact
Secondary
Reciprocal Creatinine Slope Between Month 6 and Month 18
Reciprocal Creatinine Slope is an indication of renal function over time with a higher slope value indicating an improvement in renal function.
Time frame: Between Month 6 and Month 18
Population: Full Analysis Set FAS- 145 patients were treated with study medication and had at least 1 post-baseline assessment of the primary outcome variable
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CNI-regimen | Reciprocal Creatinine Slope Between Month 6 and Month 18 | 0.045 1/(μmol/L)/(hour) | Standard Deviation 0.364 |
| CNI-free-regimen | Reciprocal Creatinine Slope Between Month 6 and Month 18 | 0.403 1/(μmol/L)/(hour) | Standard Deviation 1.863 |
p-value: 0.008Wilcoxon (Mann-Whitney)
Secondary
Serum Creatinine at Month 6, 8, 9, 10 12 and 18
Serum Creatinine is an indicator of renal function measured in the blood
Time frame: Month 6, 8, 9, 10 12 and 18
Population: Full Analysis Set FAS- 145 patients were treated with study medication and had at least 1 post-baseline assessment of the primary outcome variable
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CNI-regimen | Serum Creatinine at Month 6, 8, 9, 10 12 and 18 | Month 6 | 1.53 μmol/L | Standard Deviation 0.49 |
| CNI-regimen | Serum Creatinine at Month 6, 8, 9, 10 12 and 18 | Month 8 | 1.44 μmol/L | Standard Deviation 0.41 |
| CNI-regimen | Serum Creatinine at Month 6, 8, 9, 10 12 and 18 | Month 9 | 1.58 μmol/L | Standard Deviation 0.75 |
| CNI-regimen | Serum Creatinine at Month 6, 8, 9, 10 12 and 18 | Month 10 | 1.53 μmol/L | Standard Deviation 0.53 |
| CNI-regimen | Serum Creatinine at Month 6, 8, 9, 10 12 and 18 | Month 12 | 1.53 μmol/L | Standard Deviation 0.52 |
| CNI-regimen | Serum Creatinine at Month 6, 8, 9, 10 12 and 18 | Month 18 | 1.50 μmol/L | Standard Deviation 0.5 |
| CNI-free-regimen | Serum Creatinine at Month 6, 8, 9, 10 12 and 18 | Month 12 | 1.22 μmol/L | Standard Deviation 0.33 |
| CNI-free-regimen | Serum Creatinine at Month 6, 8, 9, 10 12 and 18 | Month 6 | 1.49 μmol/L | Standard Deviation 0.51 |
| CNI-free-regimen | Serum Creatinine at Month 6, 8, 9, 10 12 and 18 | Month 10 | 1.20 μmol/L | Standard Deviation 0.3 |
| CNI-free-regimen | Serum Creatinine at Month 6, 8, 9, 10 12 and 18 | Month 8 | 1.27 μmol/L | Standard Deviation 0.35 |
| CNI-free-regimen | Serum Creatinine at Month 6, 8, 9, 10 12 and 18 | Month 18 | 1.27 μmol/L | Standard Deviation 0.44 |
| CNI-free-regimen | Serum Creatinine at Month 6, 8, 9, 10 12 and 18 | Month 9 | 1.24 μmol/L | Standard Deviation 0.32 |