Renal Transplantation
Conditions
Keywords
Renal transplantation, everolimus, immunosuppressants, CNI-free
Brief summary
The purpose of this study is to assess whether a calcineurin inhibitor (CNI)-free regimen with enteric-coated mycophenolate sodium (EC-MPS) and everolimus is as safe and well-tolerated as the standard regimen containing enteric-coated mycophenolate sodium (EC-MPS) and cyclosporine microemulsion, but results in better renal function.
Interventions
DRUGEverolimus
Everolimus tablets orally twice a day to maintain a level of 6- 10 ng/mL.
DRUGCyclosporine
Tablets orally twice a day to maintain protocol specific target blood levels
Enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day.
DRUGCorticosteroids
Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5mg prednisolone or equivalent and had to be continued throughout the first year.
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
: The following inclusion criteria had to be present at BL 1 (Screening visit prior to transplantation): 1. Males or females, aged 18 - 65 years 2. Recipients of de novo cadaveric, living unrelated or living related kidney transplants 3. Females capable of becoming pregnant must have a negative serum pregnancy test within 7 days prior to or at BL 1, 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 4. Patients who are willing and able to participate in the study and from whom written informed consent has been obtained Of all patients included into the study at BL 1 (prior to transplantation), those who continued into the randomized study period had to meet the following condition at BL 2, prior to randomization: 5. Patients had to be on an immunosuppressive regimen with EC-MPS (target dose; 1440 mg/day, if tolerated; minimal dose: 720 mg/day), cyclosporine and corticosteroids 6. Patients with an actual serum creatinine =\< 3.0 mg/dl
Exclusion criteria
The following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Renal Function (Nankivell Formula) at Month 12 Post Transplantation. | at Month 12 post transplantation | Renal function at the end of the trial assessed as mean absolute values of the glomerular filtration rate (GFR) calculated by Nankivell formula 12 months after renal transplantation. The Nankivell formula: GFR = 6.7 / Scr + BW / 4 - Surea / 2-100 / (height)\^2 + C ; where Scr is the serum creatinine concentration expressed in mmol/L, BW the body weight in kg, Surea the serum urea in mmol/L, height in m, and the constant C is 35 for male and 25 for female patients. Estimated GFR is expressed in mL/min per 1.73m\^2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Occurrence of Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death | Up to Month 12 | The number of participants with occurrence of biopsy proven acute rejection (BPAR), graft loss, or death up to Month 12 during the randomized treatment period. BPAR was defined as a biopsy graded IA, IB, IIA, IIB or III according to Banff 97 classification. A graft core biopsy was performed prior to 24 hours following initiation of graft rejection therapy. The allograft is presumed to be lost on the day the patient starts dialysis and was not able to subsequently be removed from dialysis. If the patient underwent a graft nephrectomy, then the day of nephrectomy was the day of graft loss. |
| Number of Participants With Occurrence of Treatment Failures | up to or at Month 12 | Treatment failures defined as a composite endpoint of biopsy proven acute rejection, graft loss, death, loss to follow up and discontinuations due to lack of efficacy or toxicity, or conversion to another regimen (at least one condition must be present). |
| Changes in Cardiovascular Risk From Month 4.5 to Final Assessment at Month 12 | Month 4.5 and Month 12 | An updated 1991 Framingham coronary prediction algorithm was used to estimate the total risk of developing coronary heart diseases (CHD) over the course of 10 years. Risk was calculated separately for male and females. To calculate risk, points were assigned for each of the following risk factors: age, levels of LDL cholesterol, HDL cholesterol, blood pressure, cigarette smoking, and diabetes mellitus. The sum of the individual risk factor points gives a total point score, which ranges from -5 to 18 for men and -16 to 24 for women. Higher points indicate a higher risk for CHD. |
| Number of Participants Who Experienced an Adverse Event or Serious Adverse Event | Aes from end of core study period (month 12) to end of follow-up period (month 60) | Additional information about the number of participants who experienced Adverse Events (greater than 5%) or Serious Adverse Events can be found in the Adverse Event section. |
Countries
Germany, Switzerland
Participant flow
Recruitment details
This study was an open-label, randomized, parallel-group, multi-center study with two treatment groups, cyclosporine continuation and cyclosporine withdrawal starting from Month 4.5 post-transplant. Study started in June 2005 and ended in September 2008.
Participants by arm
| Arm | Count |
|---|---|
| Everolimus + Mycophenolate Sodium Everolimus tablets orally twice a day to maintain a level of 6- 10 ng/mL and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5 mg prednisolone or equivalent and had to be continued throughout the first year. Cyclosporine withdrawal started from Month 4.5 post-transplant. | 155 |
| Cyclosporine + Mycophenolate Sodium Cyclosporine tablets orally twice a day to achieve protocol specific target levels and enteric-coated mycophenolate sodium orally twice a day to achieve a target dose of 1440 mg/day. Corticosteroids were added to the immunosuppressive regimen with a minimum dose of 5mg prednisolone or equivalent and had to be continued throughout the first year. | 145 |
| Total | 300 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative problems | 0 | 1 |
| Overall Study | Adverse Event | 19 | 9 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Lack of Efficacy | 5 | 4 |
| Overall Study | Lost to Follow-up | 0 | 8 |
| Overall Study | Protocol Violation | 4 | 2 |
| Overall Study | Withdrawal by Subject | 9 | 3 |
Baseline characteristics
| Characteristic | Everolimus + Mycophenolate Sodium | Cyclosporine + Mycophenolate Sodium | Total |
|---|---|---|---|
| Age Continuous | 46.9 Years STANDARD_DEVIATION 11.67 | 46.7 Years STANDARD_DEVIATION 11.85 | 46.8 Years STANDARD_DEVIATION 11.73 |
| Sex: Female, Male Female | 53 Participants | 59 Participants | 112 Participants |
| Sex: Female, Male Male | 102 Participants | 86 Participants | 188 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 155 / 155 | 145 / 145 |
| serious Total, serious adverse events | 103 / 155 | 93 / 145 |
Outcome results
Primary
Renal Function (Nankivell Formula) at Month 12 Post Transplantation.
Renal function at the end of the trial assessed as mean absolute values of the glomerular filtration rate (GFR) calculated by Nankivell formula 12 months after renal transplantation. The Nankivell formula: GFR = 6.7 / Scr + BW / 4 - Surea / 2-100 / (height)\^2 + C ; where Scr is the serum creatinine concentration expressed in mmol/L, BW the body weight in kg, Surea the serum urea in mmol/L, height in m, and the constant C is 35 for male and 25 for female patients. Estimated GFR is expressed in mL/min per 1.73m\^2.
Time frame: at Month 12 post transplantation
Population: Intent to Treat Population (randomized patients); Last Observation Carried Forward (LOCF). One patient in
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Everolimus + Mycophenolate Sodium | Renal Function (Nankivell Formula) at Month 12 Post Transplantation. | 71.84 mL/min /1.73m^2 | Standard Deviation 18.53 |
| Cyclosporine + Mycophenolate Sodium | Renal Function (Nankivell Formula) at Month 12 Post Transplantation. | 61.24 mL/min /1.73m^2 | Standard Deviation 16.65 |
Secondary
Changes in Cardiovascular Risk From Month 4.5 to Final Assessment at Month 12
An updated 1991 Framingham coronary prediction algorithm was used to estimate the total risk of developing coronary heart diseases (CHD) over the course of 10 years. Risk was calculated separately for male and females. To calculate risk, points were assigned for each of the following risk factors: age, levels of LDL cholesterol, HDL cholesterol, blood pressure, cigarette smoking, and diabetes mellitus. The sum of the individual risk factor points gives a total point score, which ranges from -5 to 18 for men and -16 to 24 for women. Higher points indicate a higher risk for CHD.
Time frame: Month 4.5 and Month 12
Population: Safety Population for whom data was available at Month 4.5 and end of treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Everolimus + Mycophenolate Sodium | Changes in Cardiovascular Risk From Month 4.5 to Final Assessment at Month 12 | Male (n= 55, 37) | 0.5 Points | Standard Deviation 1.87 |
| Everolimus + Mycophenolate Sodium | Changes in Cardiovascular Risk From Month 4.5 to Final Assessment at Month 12 | Female (n= 22, 35) | 0.0 Points | Standard Deviation 2.01 |
| Everolimus + Mycophenolate Sodium | Changes in Cardiovascular Risk From Month 4.5 to Final Assessment at Month 12 | Total Population (n= 77, 72) | 0.4 Points | Standard Deviation 1.91 |
| Cyclosporine + Mycophenolate Sodium | Changes in Cardiovascular Risk From Month 4.5 to Final Assessment at Month 12 | Male (n= 55, 37) | 0.1 Points | Standard Deviation 1.86 |
| Cyclosporine + Mycophenolate Sodium | Changes in Cardiovascular Risk From Month 4.5 to Final Assessment at Month 12 | Female (n= 22, 35) | 0.8 Points | Standard Deviation 2.7 |
| Cyclosporine + Mycophenolate Sodium | Changes in Cardiovascular Risk From Month 4.5 to Final Assessment at Month 12 | Total Population (n= 77, 72) | 0.4 Points | Standard Deviation 2.32 |
Secondary
Number of Participants Who Experienced an Adverse Event or Serious Adverse Event
Additional information about the number of participants who experienced Adverse Events (greater than 5%) or Serious Adverse Events can be found in the Adverse Event section.
Time frame: Aes from end of core study period (month 12) to end of follow-up period (month 60)
Population: Safety Population consisted of all participants in whom transplantation was performed and who were treated with at least one dose of any immunosuppressive medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Everolimus + Mycophenolate Sodium | Number of Participants Who Experienced an Adverse Event or Serious Adverse Event | Adverse Events | 155 Participants |
| Everolimus + Mycophenolate Sodium | Number of Participants Who Experienced an Adverse Event or Serious Adverse Event | Serious Adverse Events | 95 Participants |
| Cyclosporine + Mycophenolate Sodium | Number of Participants Who Experienced an Adverse Event or Serious Adverse Event | Adverse Events | 145 Participants |
| Cyclosporine + Mycophenolate Sodium | Number of Participants Who Experienced an Adverse Event or Serious Adverse Event | Serious Adverse Events | 86 Participants |
Secondary
Number of Participants With Occurrence of Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death
The number of participants with occurrence of biopsy proven acute rejection (BPAR), graft loss, or death up to Month 12 during the randomized treatment period. BPAR was defined as a biopsy graded IA, IB, IIA, IIB or III according to Banff 97 classification. A graft core biopsy was performed prior to 24 hours following initiation of graft rejection therapy. The allograft is presumed to be lost on the day the patient starts dialysis and was not able to subsequently be removed from dialysis. If the patient underwent a graft nephrectomy, then the day of nephrectomy was the day of graft loss.
Time frame: Up to Month 12
Population: Intent to Treat Population (Randomized Patients)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Everolimus + Mycophenolate Sodium | Number of Participants With Occurrence of Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death | Graft Loss: Yes | 0 Participants |
| Everolimus + Mycophenolate Sodium | Number of Participants With Occurrence of Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death | BPAR: Yes | 15 Participants |
| Everolimus + Mycophenolate Sodium | Number of Participants With Occurrence of Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death | Graft Loss: No | 154 Participants |
| Everolimus + Mycophenolate Sodium | Number of Participants With Occurrence of Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death | Death: No | 154 Participants |
| Everolimus + Mycophenolate Sodium | Number of Participants With Occurrence of Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death | Death: Yes | 0 Participants |
| Everolimus + Mycophenolate Sodium | Number of Participants With Occurrence of Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death | BPAR: No | 139 Participants |
| Cyclosporine + Mycophenolate Sodium | Number of Participants With Occurrence of Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death | Death: Yes | 1 Participants |
| Cyclosporine + Mycophenolate Sodium | Number of Participants With Occurrence of Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death | Death: No | 145 Participants |
| Cyclosporine + Mycophenolate Sodium | Number of Participants With Occurrence of Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death | BPAR: Yes | 5 Participants |
| Cyclosporine + Mycophenolate Sodium | Number of Participants With Occurrence of Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death | Graft Loss: Yes | 0 Participants |
| Cyclosporine + Mycophenolate Sodium | Number of Participants With Occurrence of Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death | Graft Loss: No | 146 Participants |
| Cyclosporine + Mycophenolate Sodium | Number of Participants With Occurrence of Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death | BPAR: No | 141 Participants |
Secondary
Number of Participants With Occurrence of Treatment Failures
Treatment failures defined as a composite endpoint of biopsy proven acute rejection, graft loss, death, loss to follow up and discontinuations due to lack of efficacy or toxicity, or conversion to another regimen (at least one condition must be present).
Time frame: up to or at Month 12
Population: Intention to treat (ITT) population (Randomized Patients).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Everolimus + Mycophenolate Sodium | Number of Participants With Occurrence of Treatment Failures | Treatment failure: No | 125 Participants |
| Everolimus + Mycophenolate Sodium | Number of Participants With Occurrence of Treatment Failures | Treatment failure: Yes | 29 Participants |
| Cyclosporine + Mycophenolate Sodium | Number of Participants With Occurrence of Treatment Failures | Treatment failure: Yes | 23 Participants |
| Cyclosporine + Mycophenolate Sodium | Number of Participants With Occurrence of Treatment Failures | Treatment failure: No | 123 Participants |