Transplantation Infection
Conditions
Keywords
immunosuppression, kidney transplantation, everolimus, safety
Brief summary
The purpose of this study was to allow the continuation of everolimus treatment in patients who have completed the core study (NCT00170885) and to collect long-term safety, tolerability, and efficacy data in a group of patients treated with the upper everolimus target levels plus very low dose cyclosporin in comparison with the standard everolimus target levels plus low dose cyclosporin in patients with renal transplantation.
Interventions
DRUGEverolimus 0.25 and 0.75 mg tablets
The dose of everolimus for each patient was adjusted to achieve the target everolimus blood level range. Everolimus blood trough level was measured 5 days after any dose adjustment to verify that the blood level was within the desired target level range.
DRUGCyclosporine very low dose (150-300 ng/mL) microemulsion
The dose of cyclosporine for each patient was adjusted to achieve the target cyclosporine blood level. Cyclosporine dose adjustments were based on drug blood level determined from whole blood samples taken 2 hours (± 10 min) after the morning dose.
DRUGCyclosporine low dose (350-500 ng/mL) microemulsion
The dose of cyclosporine for each patient was adjusted to achieve the target cyclosporine blood level. Cyclosporine dose adjustments were based on drug blood level determined from whole blood samples taken 2 hours (± 10 min) after the morning dose.
Sponsors
Novartis Pharmaceuticals
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
* Patients with functioning graft who had completed the 6-month treatment period of core study * Patients who were receiving treatment with either everolimus and cyclosporin at the end of the core study * Patients who signed the informed consent of the present study extension
Exclusion criteria
\- Women who were pregnant, lactating or who wished to became pregnant. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Biopsy-proven Acute Rejection | Baseline to end of study (Month 24) | A graft core biopsy was performed on all suspected acute rejection episodes within 48 hours. Biopsies were read by the local pathologist according to the 1997 Banff criteria. A biopsy-proven acute rejection was be defined as a biopsy graded IA, IB, IIA, IIB, or III. |
| Renal Function Assessed by Creatinine Clearance | Month 12, Month 18, and Month 24 | Renal function was assessed by measuring serum creatinine and by computing creatinine clearance using the formula of Cockcroft-Gault. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Died, Number of Participants Who Lost Their Graft, and Number of Participants Who Died or Lost Their Graft | Baseline to end of study (Month 24) | A participant lost his graft if he/she started dialysis and was not able to subsequently be removed from dialysis or underwent graft nephrectomy. |
| Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) or Deaths | Baseline to end of study (Month 24) | Safety was assessed using reports of adverse events of all participants in this study. Serious adverse events are those events that resulted in death, were life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or was a congenital anomaly/birth defect. |
Participant flow
Recruitment details
This study was an 18-month extension to the 6-month core study NCT01276457. All patients who were receiving treatment at the end of the core study and signed the informed consent of the extension study were included. Patients received the same treatment in the extension study that they received in the core study.
Participants by arm
| Arm | Count |
|---|---|
| Upper Everolimus Blood Target + Very Low Dose Cyclosporine Patients received everolimus orally twice daily at a dose that was adjusted to achieve a drug blood trough level in the range of 8-12 ng/mL. Patients also received a very low dose of cyclosporine (150-300 ng/mL) orally twice daily that was adjusted to maintain a drug blood level of 200 ng/mL 2 hours after the morning dose. Both drugs were taken in the morning and again 12 hours later. The drugs were taken consistently either before, during, or after meals. No grapefruit or grapefruit juice was allowed throughout the study. | 111 |
| Standard Everolimus Blood Target + Low Dose Cyclosporine Patients received everolimus orally twice daily at a dose that was adjusted to achieve a drug blood trough level in the range of 3-8 ng/mL. Patients also received a low dose of cyclosporine (350-500 ng/mL) orally twice daily that was adjusted to maintain a drug blood level of 400 ng/mL 2 hours after the morning dose. Both drugs were taken in the morning and again 12 hours later. The drugs were taken consistently either before, during, or after meals. No grapefruit or grapefruit juice was allowed throughout the study. | 112 |
| Total | 223 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Core Study | Administrative problems | 1 | 1 |
| Core Study | Adverse Event | 6 | 3 |
| Core Study | Death | 2 | 2 |
| Core Study | Lack of Efficacy | 3 | 12 |
| Core Study | Lost to Follow-up | 1 | 2 |
| Extension Study | Death | 0 | 1 |
| Extension Study | Lack of Efficacy | 3 | 1 |
| Extension Study | Lost to Follow-up | 3 | 0 |
Baseline characteristics
| Characteristic | Upper Everolimus Blood Target + Very Low Dose Cyclosporine | Standard Everolimus Blood Target + Low Dose Cyclosporine | Total |
|---|---|---|---|
| Age Continuous | 45.3 Years STANDARD_DEVIATION 12.2 | 45.7 Years STANDARD_DEVIATION 10.2 | 45.5 Years STANDARD_DEVIATION 11.2 |
| Sex: Female, Male Female | 40 Participants | 37 Participants | 77 Participants |
| Sex: Female, Male Male | 71 Participants | 75 Participants | 146 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 142 / 142 | 142 / 143 |
| serious Total, serious adverse events | 85 / 142 | 90 / 143 |
Outcome results
Primary
Number of Participants With Biopsy-proven Acute Rejection
A graft core biopsy was performed on all suspected acute rejection episodes within 48 hours. Biopsies were read by the local pathologist according to the 1997 Banff criteria. A biopsy-proven acute rejection was be defined as a biopsy graded IA, IB, IIA, IIB, or III.
Time frame: Baseline to end of study (Month 24)
Population: Intent-to-treat (ITT) population: All randomized subjects for whom at least one valid post-baseline efficacy measurement was obtained and used for efficacy analyses.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Upper Everolimus Blood Target + Very Low Dose Cyclosporine | Number of Participants With Biopsy-proven Acute Rejection | 21 Participants |
| Standard Everolimus Blood Target + Low Dose Cyclosporine | Number of Participants With Biopsy-proven Acute Rejection | 21 Participants |
Primary
Renal Function Assessed by Creatinine Clearance
Renal function was assessed by measuring serum creatinine and by computing creatinine clearance using the formula of Cockcroft-Gault.
Time frame: Month 12, Month 18, and Month 24
Population: Intent-to-treat (ITT) population: All randomized subjects for whom at least one valid post-baseline efficacy measurement was obtained and used for efficacy analyses.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Upper Everolimus Blood Target + Very Low Dose Cyclosporine | Renal Function Assessed by Creatinine Clearance | Month 12 (n=111, 111) | 61.26 mL/min | Standard Deviation 22.06 |
| Upper Everolimus Blood Target + Very Low Dose Cyclosporine | Renal Function Assessed by Creatinine Clearance | Month 18 (n=108, 108) | 60.90 mL/min | Standard Deviation 22.85 |
| Upper Everolimus Blood Target + Very Low Dose Cyclosporine | Renal Function Assessed by Creatinine Clearance | Month 24 (n=106, 110) | 61.92 mL/min | Standard Deviation 25.37 |
| Standard Everolimus Blood Target + Low Dose Cyclosporine | Renal Function Assessed by Creatinine Clearance | Month 12 (n=111, 111) | 62.50 mL/min | Standard Deviation 20.7 |
| Standard Everolimus Blood Target + Low Dose Cyclosporine | Renal Function Assessed by Creatinine Clearance | Month 18 (n=108, 108) | 62.80 mL/min | Standard Deviation 21.18 |
| Standard Everolimus Blood Target + Low Dose Cyclosporine | Renal Function Assessed by Creatinine Clearance | Month 24 (n=106, 110) | 63.76 mL/min | Standard Deviation 21.71 |
Secondary
Number of Participants Who Died, Number of Participants Who Lost Their Graft, and Number of Participants Who Died or Lost Their Graft
A participant lost his graft if he/she started dialysis and was not able to subsequently be removed from dialysis or underwent graft nephrectomy.
Time frame: Baseline to end of study (Month 24)
Population: Safety population: All randomized subjects who took at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Upper Everolimus Blood Target + Very Low Dose Cyclosporine | Number of Participants Who Died, Number of Participants Who Lost Their Graft, and Number of Participants Who Died or Lost Their Graft | Lost graft | 6 Participants |
| Upper Everolimus Blood Target + Very Low Dose Cyclosporine | Number of Participants Who Died, Number of Participants Who Lost Their Graft, and Number of Participants Who Died or Lost Their Graft | Died or lost graft | 8 Participants |
| Upper Everolimus Blood Target + Very Low Dose Cyclosporine | Number of Participants Who Died, Number of Participants Who Lost Their Graft, and Number of Participants Who Died or Lost Their Graft | Died | 2 Participants |
| Standard Everolimus Blood Target + Low Dose Cyclosporine | Number of Participants Who Died, Number of Participants Who Lost Their Graft, and Number of Participants Who Died or Lost Their Graft | Died | 3 Participants |
| Standard Everolimus Blood Target + Low Dose Cyclosporine | Number of Participants Who Died, Number of Participants Who Lost Their Graft, and Number of Participants Who Died or Lost Their Graft | Died or lost graft | 18 Participants |
| Standard Everolimus Blood Target + Low Dose Cyclosporine | Number of Participants Who Died, Number of Participants Who Lost Their Graft, and Number of Participants Who Died or Lost Their Graft | Lost graft | 15 Participants |
Secondary
Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) or Deaths
Safety was assessed using reports of adverse events of all participants in this study. Serious adverse events are those events that resulted in death, were life threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or was a congenital anomaly/birth defect.
Time frame: Baseline to end of study (Month 24)
Population: Safety population: All randomized subjects who took at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Upper Everolimus Blood Target + Very Low Dose Cyclosporine | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) or Deaths | Infection | 95 Partcipants |
| Upper Everolimus Blood Target + Very Low Dose Cyclosporine | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) or Deaths | SAEs | 85 Partcipants |
| Upper Everolimus Blood Target + Very Low Dose Cyclosporine | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) or Deaths | Clinically significant AEs | 58 Partcipants |
| Upper Everolimus Blood Target + Very Low Dose Cyclosporine | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) or Deaths | Died | 2 Partcipants |
| Upper Everolimus Blood Target + Very Low Dose Cyclosporine | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) or Deaths | AEs | 142 Partcipants |
| Standard Everolimus Blood Target + Low Dose Cyclosporine | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) or Deaths | Died | 3 Partcipants |
| Standard Everolimus Blood Target + Low Dose Cyclosporine | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) or Deaths | AEs | 143 Partcipants |
| Standard Everolimus Blood Target + Low Dose Cyclosporine | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) or Deaths | Infection | 101 Partcipants |
| Standard Everolimus Blood Target + Low Dose Cyclosporine | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) or Deaths | Clinically significant AEs | 53 Partcipants |
| Standard Everolimus Blood Target + Low Dose Cyclosporine | Number of Participants With Adverse Events (AE), Serious Adverse Events (SAE) or Deaths | SAEs | 90 Partcipants |