Heart Transplantation
Conditions
Keywords
allograft rejection, xenograft rejection, host vs graft disease, transplant
Brief summary
The major aim of this extension study was to evaluate the long-term effect (i.e. 5 to 7 years) of early initiation of everolimus and early elimination of CsA compared to standard immunosuppressive regimen including CsA on primary and secondary endpoints investigated in the SCHEDULE (NCT01266148) main study.
Detailed description
This protocol was written to describe the procedures for a single 5, 6 or 7 year follow-up control visit of patients who participated in the 12-month SCHEDULE (NCT01266148) study and the following 3-year follow-up examination/visit. The aim of this 5 to 7-year follow-up visit was to examine the effect of long term treatment, i.e. 5, 6 or 7 years, with early initiation of everolimus (Certican®) and early elimination of cyclosporine (CsA), compared to standard immunosuppressive regimen including CsA, on renal and heart function. During the time period of this follow-up examinations, this visit was performed as part of a routine annual visit 5, 6 or 7 years since transplantation (and inclusion in the original SCHEDULE study). Study code of SCHEDULE, the core study: CRAD001ANO02 (EudraCT No.: 2009-013074-41)
Interventions
DRUGEverolimus
All patients, independent of their initial randomization in the core study, were followed up as in one single group Commercially available everolimus (Certican®), oral route, was used.
DRUGCyclosporine
Cyclosporine (CsA) control group target blood level: 150-350 ng/mL (month 1-3); 100-250 ng/mL (month 4-6); 60-200 ng/mL (month 7-12); everolimus group target blood level: 75-175 ng/mL (month 1-3)
DRUGMycophenolate mofetil
Mycophenolate mofetil (MMF) target dose for control group: 2000-3000 mg/day everolimus group target dose: 1500-2000 mg/day and 75-175 ng/mL after week 11
DRUGCorticosteroids
Corticosteroids (CS) initiated at 0.2-0.5 mg/kg/day. Tapered to no less than 0.1 mg/kg at Month 3 for control and everolimus groups.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Patients who participated in the SCHEDULE 12-month main study, and who completed the 3 year follow-up visit * Patients who are coming for a regular annual clinic visit 5 to 7 years after randomization in the main study * Obtaining of a separate signed patient informed consent will be required for participation in this follow-up examination.
Exclusion criteria
* Patients with a retransplanted heart since the original SCHEDULE study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Measured Glomerular Filtration Rate (mGFR) | at the 5-7 year follow-up visit | Renal function as assessed by measured Glomerular Filtration Rate (mGFR) (Cr-EDTA or iohexol clearance). Baseline Visit 1 and Patient 4252 excluded from the intent treat analysis set. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent of Participants With Incidence of Coronary Allograft Vasculopathy (CAV) | at the 5-7 year follow-up | Cardiac Allograft Vasculopathy (CAV) was defined as mean maximal intimal thickness (MIT) ≥0.5 mm, measured for the entire matched pullback recording by intravascular ultrasound (IVUS). The incidence of CAV at 5-7 years was compared between groups using the Cochran-Mantel-Haenszel test with stratification according to baseline distribution of CAV incidence. |
| Myocardial Structure and Function | within 5-7 years | Myocardial structure and function by echocardiography assessment measured by ventricular end systolic diameter. |
| Quality of Life by SF-36 Change From Pre-transplantation to 5-7 Year Follow-up | at the 5-7 year visit | This Quality of life Short Form Survey with 36 items (Minnesota Living with Heart Failure Questionnaire)was administered to patients pre-transplantation and after transplantation at the 5-7 year visit. This data represents the change. The survey consist of scores on a scale. Each form is scaled from 0 t 100. 0 = maximum disability and 100 equals no disability. |
| Progression of Cardiac Allograft Vasculopathy (CAV) Recorded by Intravascular Ultrasound (IVUS) | within 5-7 years | Cardiac Allograft Vasculopathy (CAV) was defined as mean maximal intimal thickness (MIT) ≥0.5 mm, measured for the entire matched pullback recording by intravascular ultrasound (IVUS). The incidence of CAV at 5-7 years was compared between groups using the Cochran-Mantel-Haenszel test with stratification according to baseline distribution of CAV incidence. |
| Change From Baseline in Visual Analog Scale (VAS) | baseline, at the 5-7 year visit | Change in visual analog scale (VAS) from baseline to the 5 to 7 Year follow up visit. 0 is no pain; and 10 is the worst possible pain |
| Number of Participants With Beck Depression Inventory (BDI) | at the 5-7 year visit | Beck Depression Inventory (BDI) Score has the following categories of depression. Normal, Mild, Moderate Severe and Missing. |
| Change From Baseline in the Euro Quality of Life 5D | Baseline, 5-7 year visit | Change from baseline in Euro Quality of Life-5D from 3 Year Follow-Up to 5 to 7 Year Follow-Up Baseline Visit 1 (ITT Set) Euro Quality of Life 5D (EQ-5D): is a descriptive system of healthrelated quality of life states consisting of five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) each of which can be assessed as one of three levels of severity (no problems/some or moderate problems/extreme problems). A Visual Analogue Scale (VAS)-scale is also included in the EQ-5D questionnaire. The EQ-5D index is calculated based on the United Kingdom Time Trade-Off (TTO) N3 value set which converts the five dimensions scores into a single measure with a possible range from -0.163 (worst possible health state) to +1 (perfect health). A positive change from baseline indicates an improvement in Quality of Life. |
Countries
Denmark, Norway, Sweden
Participant flow
Recruitment details
In total, 95 patients (48 everolimus, 47 controls), attended the follow-up visit at 5-7 years post-transplant and were included in the safety population The PP population (27 everolimus, 35 controls) excluded 7 patients in the everolimus group and 11 in the control group who discontinued study drug prematurely
Pre-assignment details
Two patients randomized to everolimus did not provide a month 12 measured GFR (mGFR) value and were excluded from the ITT population, which thus comprised 93 patients (46 everolimus, 47 controls).
Participants by arm
| Arm | Count |
|---|---|
| Everolimus patients received everolimus (Certican), low-exposure CsA (Neoral), mycophenolate mofetil (MMF) and corticosteroids with CsA withdrawal after 7-11 weeks | 48 |
| Control patients received standard CsA, MMF and corticosteroids | 47 |
| Total | 95 |
Baseline characteristics
| Characteristic | Control | Total | Everolimus |
|---|---|---|---|
| Age, Continuous | 52.11 Years STANDARD_DEVIATION 11.61 | 51.11 Years STANDARD_DEVIATION 12.53 | 50.13 Years STANDARD_DEVIATION 13.43 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 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 | 44 Participants | 91 Participants | 47 Participants |
| Sex: Female, Male Female | 12 Participants | 25 Participants | 13 Participants |
| Sex: Female, Male Male | 35 Participants | 70 Participants | 35 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 48 | 0 / 47 |
| other Total, other adverse events | 15 / 48 | 4 / 47 |
| serious Total, serious adverse events | 26 / 48 | 18 / 47 |
Outcome results
Primary
Measured Glomerular Filtration Rate (mGFR)
Renal function as assessed by measured Glomerular Filtration Rate (mGFR) (Cr-EDTA or iohexol clearance). Baseline Visit 1 and Patient 4252 excluded from the intent treat analysis set.
Time frame: at the 5-7 year follow-up visit
Population: intent to treat. 1 patient was excluded from ITT due to missing mGFR.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Everolimus | Measured Glomerular Filtration Rate (mGFR) | 74.7 mL/min/1.73m2 | Standard Deviation 23.3 |
| Control | Measured Glomerular Filtration Rate (mGFR) | 62.4 mL/min/1.73m2 | Standard Deviation 16.5 |
p-value: 0.0043ANCOVA
Secondary
Change From Baseline in the Euro Quality of Life 5D
Change from baseline in Euro Quality of Life-5D from 3 Year Follow-Up to 5 to 7 Year Follow-Up Baseline Visit 1 (ITT Set) Euro Quality of Life 5D (EQ-5D): is a descriptive system of healthrelated quality of life states consisting of five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) each of which can be assessed as one of three levels of severity (no problems/some or moderate problems/extreme problems). A Visual Analogue Scale (VAS)-scale is also included in the EQ-5D questionnaire. The EQ-5D index is calculated based on the United Kingdom Time Trade-Off (TTO) N3 value set which converts the five dimensions scores into a single measure with a possible range from -0.163 (worst possible health state) to +1 (perfect health). A positive change from baseline indicates an improvement in Quality of Life.
Time frame: Baseline, 5-7 year visit
Population: intent to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Everolimus | Change From Baseline in the Euro Quality of Life 5D | 0.2323 scores on the scale | Standard Deviation 0.3849 |
| Control | Change From Baseline in the Euro Quality of Life 5D | 0.2982 scores on the scale | Standard Deviation 0.3274 |
Secondary
Change From Baseline in Visual Analog Scale (VAS)
Change in visual analog scale (VAS) from baseline to the 5 to 7 Year follow up visit. 0 is no pain; and 10 is the worst possible pain
Time frame: baseline, at the 5-7 year visit
Population: Intent to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Everolimus | Change From Baseline in Visual Analog Scale (VAS) | 35.6 mm | Standard Deviation 26.9 |
| Control | Change From Baseline in Visual Analog Scale (VAS) | 34.0 mm | Standard Deviation 32 |
Secondary
Myocardial Structure and Function
Myocardial structure and function by echocardiography assessment measured by ventricular end systolic diameter.
Time frame: within 5-7 years
Population: intent to treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Everolimus | Myocardial Structure and Function | LVESD (left ventricular end systolic diameter) | 3.1 cm | Standard Deviation 0.8 |
| Everolimus | Myocardial Structure and Function | LVEDD (left ventricular end diastolic diameter) | 4.7 cm | Standard Deviation 0.6 |
| Control | Myocardial Structure and Function | LVESD (left ventricular end systolic diameter) | 3.1 cm | Standard Deviation 0.6 |
| Control | Myocardial Structure and Function | LVEDD (left ventricular end diastolic diameter) | 4.9 cm | Standard Deviation 0.6 |
Secondary
Number of Participants With Beck Depression Inventory (BDI)
Beck Depression Inventory (BDI) Score has the following categories of depression. Normal, Mild, Moderate Severe and Missing.
Time frame: at the 5-7 year visit
Population: ITT
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Everolimus | Number of Participants With Beck Depression Inventory (BDI) | Mild | 6 Participants |
| Everolimus | Number of Participants With Beck Depression Inventory (BDI) | Severe | 1 Participants |
| Everolimus | Number of Participants With Beck Depression Inventory (BDI) | Moderate | 2 Participants |
| Everolimus | Number of Participants With Beck Depression Inventory (BDI) | Missing | 3 Participants |
| Everolimus | Number of Participants With Beck Depression Inventory (BDI) | Normal | 15 Participants |
| Control | Number of Participants With Beck Depression Inventory (BDI) | Missing | 5 Participants |
| Control | Number of Participants With Beck Depression Inventory (BDI) | Normal | 13 Participants |
| Control | Number of Participants With Beck Depression Inventory (BDI) | Mild | 4 Participants |
| Control | Number of Participants With Beck Depression Inventory (BDI) | Moderate | 5 Participants |
| Control | Number of Participants With Beck Depression Inventory (BDI) | Severe | 0 Participants |
Secondary
Percent of Participants With Incidence of Coronary Allograft Vasculopathy (CAV)
Cardiac Allograft Vasculopathy (CAV) was defined as mean maximal intimal thickness (MIT) ≥0.5 mm, measured for the entire matched pullback recording by intravascular ultrasound (IVUS). The incidence of CAV at 5-7 years was compared between groups using the Cochran-Mantel-Haenszel test with stratification according to baseline distribution of CAV incidence.
Time frame: at the 5-7 year follow-up
Population: Intent to Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus | Percent of Participants With Incidence of Coronary Allograft Vasculopathy (CAV) | 53 percent of participants |
| Control | Percent of Participants With Incidence of Coronary Allograft Vasculopathy (CAV) | 74 percent of participants |
Secondary
Progression of Cardiac Allograft Vasculopathy (CAV) Recorded by Intravascular Ultrasound (IVUS)
Cardiac Allograft Vasculopathy (CAV) was defined as mean maximal intimal thickness (MIT) ≥0.5 mm, measured for the entire matched pullback recording by intravascular ultrasound (IVUS). The incidence of CAV at 5-7 years was compared between groups using the Cochran-Mantel-Haenszel test with stratification according to baseline distribution of CAV incidence.
Time frame: within 5-7 years
Population: Intent to Treat.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Everolimus | Progression of Cardiac Allograft Vasculopathy (CAV) Recorded by Intravascular Ultrasound (IVUS) | 0.13 mm | Standard Deviation 0.15 |
| Control | Progression of Cardiac Allograft Vasculopathy (CAV) Recorded by Intravascular Ultrasound (IVUS) | 0.23 mm | Standard Deviation 0.24 |
p-value: 0.037Cochran-Mantel-Haenszel
Secondary
Quality of Life by SF-36 Change From Pre-transplantation to 5-7 Year Follow-up
This Quality of life Short Form Survey with 36 items (Minnesota Living with Heart Failure Questionnaire)was administered to patients pre-transplantation and after transplantation at the 5-7 year visit. This data represents the change. The survey consist of scores on a scale. Each form is scaled from 0 t 100. 0 = maximum disability and 100 equals no disability.
Time frame: at the 5-7 year visit
Population: intent to treat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Everolimus | Quality of Life by SF-36 Change From Pre-transplantation to 5-7 Year Follow-up | Physical Health Summary | 16.8 scores on a scale | Standard Deviation 15 |
| Everolimus | Quality of Life by SF-36 Change From Pre-transplantation to 5-7 Year Follow-up | Mental Health Summary | 10.4 scores on a scale | Standard Deviation 10.5 |
| Everolimus | Quality of Life by SF-36 Change From Pre-transplantation to 5-7 Year Follow-up | Physical Functioning | 36.7 scores on a scale | Standard Deviation 38.4 |
| Everolimus | Quality of Life by SF-36 Change From Pre-transplantation to 5-7 Year Follow-up | Role Physical | 50.2 scores on a scale | Standard Deviation 32.3 |
| Everolimus | Quality of Life by SF-36 Change From Pre-transplantation to 5-7 Year Follow-up | Bodily Pain | 10.3 scores on a scale | Standard Deviation 34.8 |
| Everolimus | Quality of Life by SF-36 Change From Pre-transplantation to 5-7 Year Follow-up | General Health | 25.7 scores on a scale | Standard Deviation 26.4 |
| Everolimus | Quality of Life by SF-36 Change From Pre-transplantation to 5-7 Year Follow-up | Vitality | 30.0 scores on a scale | Standard Deviation 25.8 |
| Everolimus | Quality of Life by SF-36 Change From Pre-transplantation to 5-7 Year Follow-up | Social Functioning | 39.9 scores on a scale | Standard Deviation 31.5 |
| Everolimus | Quality of Life by SF-36 Change From Pre-transplantation to 5-7 Year Follow-up | Role Emotional | 23.8 scores on a scale | Standard Deviation 36.7 |
| Everolimus | Quality of Life by SF-36 Change From Pre-transplantation to 5-7 Year Follow-up | Mental Health | 8.6 scores on a scale | Standard Deviation 17.2 |
| Control | Quality of Life by SF-36 Change From Pre-transplantation to 5-7 Year Follow-up | Social Functioning | 43.9 scores on a scale | Standard Deviation 32.4 |
| Control | Quality of Life by SF-36 Change From Pre-transplantation to 5-7 Year Follow-up | Physical Health Summary | 13.2 scores on a scale | Standard Deviation 13.3 |
| Control | Quality of Life by SF-36 Change From Pre-transplantation to 5-7 Year Follow-up | General Health | 23.4 scores on a scale | Standard Deviation 25.6 |
| Control | Quality of Life by SF-36 Change From Pre-transplantation to 5-7 Year Follow-up | Mental Health Summary | 15.3 scores on a scale | Standard Deviation 15.5 |
| Control | Quality of Life by SF-36 Change From Pre-transplantation to 5-7 Year Follow-up | Mental Health | 14.4 scores on a scale | Standard Deviation 25.8 |
| Control | Quality of Life by SF-36 Change From Pre-transplantation to 5-7 Year Follow-up | Physical Functioning | 40.8 scores on a scale | Standard Deviation 30.4 |
| Control | Quality of Life by SF-36 Change From Pre-transplantation to 5-7 Year Follow-up | Vitality | 28.9 scores on a scale | Standard Deviation 29 |
| Control | Quality of Life by SF-36 Change From Pre-transplantation to 5-7 Year Follow-up | Role Physical | 55.1 scores on a scale | Standard Deviation 32.4 |
| Control | Quality of Life by SF-36 Change From Pre-transplantation to 5-7 Year Follow-up | Role Emotional | 42.8 scores on a scale | Standard Deviation 46.5 |
| Control | Quality of Life by SF-36 Change From Pre-transplantation to 5-7 Year Follow-up | Bodily Pain | 7.2 scores on a scale | Standard Deviation 34.1 |