Cardiac Transplantation
Conditions
Brief summary
The purpose of this study, in de novo heart transplant patients, is to evaluate whether delayed introduction of everolimus reduces the occurrence of wound healing problems, pericardial and/or pleural effusion and early acute renal insufficiency, as compared with immediate introduction of everolimus, in the firs six months after heart transplantation.
Interventions
DRUGEverolimus
DRUGMycophenolate mofetil + Everolimus
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Male or female cardiac transplant candidates 18-65 years of age undergoing primary heart transplantation. * Glomerular filtration rate (GFR by MDRD) ≥ 40 mL/min/1.73 m2 at randomization
Exclusion criteria
* Patients who are recipients of multiple solid organ transplants * Patients who are HIV-positive or Hepatitis C positive (PCR only) or B-surface antigen positive; * Presence of Donor/Recipients serological mismatch for Hepatitis B or C; * Recipients of organ from donors positive for Hepatitis B-surface antigen; * Panel Reactive Antibodies (cytotoxicity method) \> 30%. * Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants With at Least One Occurrence of Safety Composite Endpoint After 6 Months by Treatment Group | 6 months | Comparison of 6-month cumulative incidence of safety composite endpoint (wound healing delay) related to initial transplant surgery, pleural/pericardial effusions and occurrence of acute renal insufficiency, defined as estimated glomerular filtration rate (eGFR) ≤ 30 mL/min/1.73 m2, between delayed everolimus arm and immediate everolimus arm |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Partcipants With at Least One Occurrence of Each Safety Composite Endpoint Event After 6 Months by Treatment Group | 6 months | — |
| Hazard Cox's Model Analysis of Pericardial/Pleural Effusions | 6 months | Pericardial effusions: any pericardial effusion defined as at least moderate (i.e. measuring at least 2.0 cm in diastole, in the point of largest distance between the pericardial leaflets), with or without signs of hemodynamic compromise, or leading to drainage or to prolonged hospitalization. Pleural effusions: need for surgical drainage tubes for longer than 7 days after surgery and subsequent pleural effusions leading to drainage. CI = confidence interval, HR = hazard ratio, MDRD = Modification of Diet in Renal Disease |
| Absolute and Percent Frequencies of Patients With LDL ≥ 100 mg/mL at 1, 3 and 6 Months, by Treatment Group | 6 months | LDL = low density lipoprotein |
| Participants With CMV Infection and CMV Syndrome/Disease After 6 Months by Treatment Group | 6 months | CMV infection is defined as pp65 antigenemia or DNAemia |
| Participants With at Least One Occurrence of Composite Treatment Failure Events | 6 months | Comparison of 6-months cumulative incidence of composite treatment failure events (BPAR ≥ 2R, rejection with hemodynamic compromise, graft loss, or death) between delayed everolimus arm and immediate everolimus arm |
Countries
Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Immediate Introduction of Everolimus Everolimus within 144 hours (5 days) after graft reperfusion + cyclosporine microemulsion + steroids | 89 |
| Delayed Introduction of Everolimus Mycophenolate mofetil (MMF) within 144 hours (5 days) after graft reperfusion + cyclosporine microemulsion + steroids. After 4 to 6 weeks since transplant, everolimus in place of MMF and dose of cyclosporine reduced. | 92 |
| Total | 181 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative problem | 0 | 1 |
| Overall Study | Death | 3 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
Baseline characteristics
| Characteristic | Immediate Introduction of Everolimus | Delayed Introduction of Everolimus | Total |
|---|---|---|---|
| Age, Continuous | 52.69 years STANDARD_DEVIATION 10.15 | 52.95 years STANDARD_DEVIATION 10.19 | 52.82 years STANDARD_DEVIATION 10.14 |
| Calculated BMI | 25.44 kg/m2* STANDARD_DEVIATION 3.65 | 24.48 kg/m2* STANDARD_DEVIATION 3.33 | 24.95 kg/m2* STANDARD_DEVIATION 3.52 |
| Height | 170.80 centimeters STANDARD_DEVIATION 7.69 | 170.10 centimeters STANDARD_DEVIATION 8.03 | 170.44 centimeters STANDARD_DEVIATION 7.85 |
| Race/Ethnicity, Customized Black | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Caucasian | 88 participants | 88 participants | 176 participants |
| Race/Ethnicity, Customized Other | 1 participants | 3 participants | 4 participants |
| Sex: Female, Male Female | 16 Participants | 21 Participants | 37 Participants |
| Sex: Female, Male Male | 73 Participants | 71 Participants | 144 Participants |
| Weight | 74.38 kilograms STANDARD_DEVIATION 12.5 | 71.18 kilograms STANDARD_DEVIATION 12.75 | 72.76 kilograms STANDARD_DEVIATION 12.7 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 72 / 89 | 68 / 92 |
| serious Total, serious adverse events | 35 / 89 | 31 / 92 |
Outcome results
Primary
Participants With at Least One Occurrence of Safety Composite Endpoint After 6 Months by Treatment Group
Comparison of 6-month cumulative incidence of safety composite endpoint (wound healing delay) related to initial transplant surgery, pleural/pericardial effusions and occurrence of acute renal insufficiency, defined as estimated glomerular filtration rate (eGFR) ≤ 30 mL/min/1.73 m2, between delayed everolimus arm and immediate everolimus arm
Time frame: 6 months
Population: safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Introduction of Everolimus | Participants With at Least One Occurrence of Safety Composite Endpoint After 6 Months by Treatment Group | 40 participants |
| Delayed Introduction of Everolimus | Participants With at Least One Occurrence of Safety Composite Endpoint After 6 Months by Treatment Group | 30 participants |
p-value: 0.104395% CI: [0.922, 2.383]Regression, Cox
Secondary
Absolute and Percent Frequencies of Patients With LDL ≥ 100 mg/mL at 1, 3 and 6 Months, by Treatment Group
LDL = low density lipoprotein
Time frame: 6 months
Population: safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Immediate Introduction of Everolimus | Absolute and Percent Frequencies of Patients With LDL ≥ 100 mg/mL at 1, 3 and 6 Months, by Treatment Group | Month 1 | 41 participants |
| Immediate Introduction of Everolimus | Absolute and Percent Frequencies of Patients With LDL ≥ 100 mg/mL at 1, 3 and 6 Months, by Treatment Group | Month 3 | 37 participants |
| Immediate Introduction of Everolimus | Absolute and Percent Frequencies of Patients With LDL ≥ 100 mg/mL at 1, 3 and 6 Months, by Treatment Group | Month 6 | 34 participants |
| Delayed Introduction of Everolimus | Absolute and Percent Frequencies of Patients With LDL ≥ 100 mg/mL at 1, 3 and 6 Months, by Treatment Group | Month 1 | 38 participants |
| Delayed Introduction of Everolimus | Absolute and Percent Frequencies of Patients With LDL ≥ 100 mg/mL at 1, 3 and 6 Months, by Treatment Group | Month 3 | 37 participants |
| Delayed Introduction of Everolimus | Absolute and Percent Frequencies of Patients With LDL ≥ 100 mg/mL at 1, 3 and 6 Months, by Treatment Group | Month 6 | 36 participants |
Secondary
Hazard Cox's Model Analysis of Pericardial/Pleural Effusions
Pericardial effusions: any pericardial effusion defined as at least moderate (i.e. measuring at least 2.0 cm in diastole, in the point of largest distance between the pericardial leaflets), with or without signs of hemodynamic compromise, or leading to drainage or to prolonged hospitalization. Pleural effusions: need for surgical drainage tubes for longer than 7 days after surgery and subsequent pleural effusions leading to drainage. CI = confidence interval, HR = hazard ratio, MDRD = Modification of Diet in Renal Disease
Time frame: 6 months
Population: safety population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Introduction of Everolimus | Hazard Cox's Model Analysis of Pericardial/Pleural Effusions | 30 participants |
| Delayed Introduction of Everolimus | Hazard Cox's Model Analysis of Pericardial/Pleural Effusions | 18 participants |
p-value: 0.039895% CI: [1.029, 3.315]Regression, Cox
Secondary
Partcipants With at Least One Occurrence of Each Safety Composite Endpoint Event After 6 Months by Treatment Group
Time frame: 6 months
Population: safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Immediate Introduction of Everolimus | Partcipants With at Least One Occurrence of Each Safety Composite Endpoint Event After 6 Months by Treatment Group | Wound healing complication | 10 participants |
| Immediate Introduction of Everolimus | Partcipants With at Least One Occurrence of Each Safety Composite Endpoint Event After 6 Months by Treatment Group | Pleural effusion | 1 participants |
| Immediate Introduction of Everolimus | Partcipants With at Least One Occurrence of Each Safety Composite Endpoint Event After 6 Months by Treatment Group | Pericardial effusion | 30 participants |
| Immediate Introduction of Everolimus | Partcipants With at Least One Occurrence of Each Safety Composite Endpoint Event After 6 Months by Treatment Group | eGFR ≤ 30 mL/min/1.73 m2 | 7 participants |
| Delayed Introduction of Everolimus | Partcipants With at Least One Occurrence of Each Safety Composite Endpoint Event After 6 Months by Treatment Group | eGFR ≤ 30 mL/min/1.73 m2 | 8 participants |
| Delayed Introduction of Everolimus | Partcipants With at Least One Occurrence of Each Safety Composite Endpoint Event After 6 Months by Treatment Group | Wound healing complication | 8 participants |
| Delayed Introduction of Everolimus | Partcipants With at Least One Occurrence of Each Safety Composite Endpoint Event After 6 Months by Treatment Group | Pericardial effusion | 18 participants |
| Delayed Introduction of Everolimus | Partcipants With at Least One Occurrence of Each Safety Composite Endpoint Event After 6 Months by Treatment Group | Pleural effusion | 1 participants |
Secondary
Participants With at Least One Occurrence of Composite Treatment Failure Events
Comparison of 6-months cumulative incidence of composite treatment failure events (BPAR ≥ 2R, rejection with hemodynamic compromise, graft loss, or death) between delayed everolimus arm and immediate everolimus arm
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Introduction of Everolimus | Participants With at Least One Occurrence of Composite Treatment Failure Events | 33 participants |
| Delayed Introduction of Everolimus | Participants With at Least One Occurrence of Composite Treatment Failure Events | 26 participants |
p-value: 0.196695% CI: [0.839, 2.347]Regression, Cox
Secondary
Participants With CMV Infection and CMV Syndrome/Disease After 6 Months by Treatment Group
CMV infection is defined as pp65 antigenemia or DNAemia
Time frame: 6 months
Population: safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Immediate Introduction of Everolimus | Participants With CMV Infection and CMV Syndrome/Disease After 6 Months by Treatment Group | CMV infections | 46 participants |
| Immediate Introduction of Everolimus | Participants With CMV Infection and CMV Syndrome/Disease After 6 Months by Treatment Group | CMV syndrome/disease | 3 participants |
| Delayed Introduction of Everolimus | Participants With CMV Infection and CMV Syndrome/Disease After 6 Months by Treatment Group | CMV infections | 63 participants |
| Delayed Introduction of Everolimus | Participants With CMV Infection and CMV Syndrome/Disease After 6 Months by Treatment Group | CMV syndrome/disease | 6 participants |
Comparison: CMV infectionsp-value: 0.0234Fisher Exact