Renal Transplantation
Conditions
Keywords
Renal transplantation, everolimus, immunosuppressants, wound-healing
Brief summary
The purpose of this study is to evaluate if the delayed administration of everolimus could reduce the everolimus associated anti-proliferative complications (e.g. wound healing disorder) while maintaining efficacy, when compared to the immediate administration of everolimus in de novo renal transplant patients.
Interventions
DRUGEverolimus (RAD001)
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Recipients of cadaveric kidney transplants * Patients at risk of DGF defined as one or more of the following: * Donor age \> 55 years * Cold ischemic time (CIT) ≥ 24 hours but \< 40 hours * Second or subsequent renal transplantation
Exclusion criteria
* Patients who have received an investigational drug within 4 weeks of baseline period * Patients who are recipients of multiple organ transplants, including more than one kidney, or previous transplant with any organ other than kidney * Patients with body mass index (BMI) \> 32 kg/m2 Other protocol-defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Considered in Failure for the Primary Failure Endpoint at 3 Months | Month 3 | In Failure, is at least one of these events occurred within the first 3 months: delayed graft function(DGF), (need for dialysis within the first 7 days,minus day one,post-transplantation); Biopsy proven acute rejection (BPAR), Graft loss, (allograft was presumed lost on the day the patient started and not removable from dialysis). Death; Loss to follow-up; Wound healing disorder(Any wound related to the kidney transplantation being opened beyond 3 weeks, or infected, or drained fluid or herniated was considered not healed). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Considered in Failure for the Primary Failure Endpoint at 6 Months Post-transplantation. | at 6 Month post-transplantation | The primary efficacy variable was the primary failure endpoint at 6 months defined as the occurrence of one or more of the following events within the first 6 months: * delayed graft function (DGF), defined as the need for dialysis within the first 7 days post-transplantation excluding the first day post-transplantation * efficacy failure (biopsy proven acute rejection (BPAR), graft loss, death or loss to follow-up) * wound healing disorder related to initial transplant surgery |
| Number of Participants Considered in Failure for the Primary Failure Endpoint at 12 Months Post-transplantation. | at 12 Month post-transplantation | The primary efficacy variable was the primary failure endpoint at 12 months defined as the occurrence of one or more of the following events within the first 12 months: * delayed graft function (DGF), defined as the need for dialysis within the first 7 days post-transplantation excluding the first day post-transplantation * efficacy failure (biopsy proven acute rejection (BPAR), graft loss, death or loss to follow-up) * wound healing disorder related to initial transplant surgery |
| Number of Participants Who Underwent Any Dialysis Within the 12-month Treatment Period | Month 12 | The number of patients who underwent any dialysis within the 12-month treatment period. |
| Duration of Dialysis | 12 months | The mean duration in days of any dialysis session that occurred within the 12 month treatment period. |
| Number of Participants With Any Wound Healing Disorder During the 12-month Treatment Period | Month 12 | A wound was considered healed if all the suture material and staples were removed and the wound was intact by 3 weeks. Any wound opened beyond this point, infected, drained fluid or herniated was considered not healed. |
Countries
Switzerland
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Immediate Everolimus Patients received Everolimus starting within 48 hours of kidney transplant through to the end of the study, administered orally twice a day. Dose was adjusted in order to maintain a trough level between 3-8 ng/mL. | 65 |
| Delayed Everolimus Patients received Everolimus 4 weeks after kidney transplant until the end of the study, administered orally twice a day. The dose was adjusted in order to maintain a trough level between 3-8 ng/mL. Patients received mycophenolic acid until everolimus was initiated. | 74 |
| Total | 139 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 5 | 2 |
| Overall Study | Lost to Follow-up | 3 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 5 |
Baseline characteristics
| Characteristic | Immediate Everolimus | Delayed Everolimus | Total |
|---|---|---|---|
| Age Continuous | 57.3 years STANDARD_DEVIATION 10.46 | 58.4 years STANDARD_DEVIATION 9.86 | 57.9 years STANDARD_DEVIATION 10.13 |
| Sex: Female, Male Female | 19 Participants | 20 Participants | 39 Participants |
| Sex: Female, Male Male | 46 Participants | 54 Participants | 100 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 64 / 65 | 70 / 74 |
| serious Total, serious adverse events | 45 / 65 | 57 / 74 |
Outcome results
Primary
Number of Participants Considered in Failure for the Primary Failure Endpoint at 3 Months
In Failure, is at least one of these events occurred within the first 3 months: delayed graft function(DGF), (need for dialysis within the first 7 days,minus day one,post-transplantation); Biopsy proven acute rejection (BPAR), Graft loss, (allograft was presumed lost on the day the patient started and not removable from dialysis). Death; Loss to follow-up; Wound healing disorder(Any wound related to the kidney transplantation being opened beyond 3 weeks, or infected, or drained fluid or herniated was considered not healed).
Time frame: Month 3
Population: Intention to treat (ITT) population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 3 Months | --BPAR | 7 Participants |
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 3 Months | --Death | 4 Participants |
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 3 Months | Efficacy failure (Total) | 14 Participants |
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 3 Months | --Lost to follow-up (composite efficacy endpoint) | 0 Participants |
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 3 Months | --Graft Loss | 5 Participants |
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 3 Months | Wound healing disorder | 24 Participants |
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 3 Months | Dialysis within first 7 days | 16 Participants |
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 3 Months | Loss to follow-up for the primary failure endpoint | 0 Participants |
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 3 Months | Failure at month 3 - Total | 36 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 3 Months | Loss to follow-up for the primary failure endpoint | 3 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 3 Months | Failure at month 3 - Total | 47 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 3 Months | Efficacy failure (Total) | 15 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 3 Months | --BPAR | 7 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 3 Months | --Graft Loss | 3 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 3 Months | Dialysis within first 7 days | 18 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 3 Months | --Death | 2 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 3 Months | --Lost to follow-up (composite efficacy endpoint) | 4 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 3 Months | Wound healing disorder | 28 Participants |
Secondary
Duration of Dialysis
The mean duration in days of any dialysis session that occurred within the 12 month treatment period.
Time frame: 12 months
Population: The number of patients analyzed includes those with any dialysis in the 12 month period
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Immediate Everolimus | Duration of Dialysis | 11.9 Days | Standard Deviation 7.01 |
| Delayed Everolimus | Duration of Dialysis | 7.8 Days | Standard Deviation 7.42 |
Secondary
Number of Participants Considered in Failure for the Primary Failure Endpoint at 12 Months Post-transplantation.
The primary efficacy variable was the primary failure endpoint at 12 months defined as the occurrence of one or more of the following events within the first 12 months: * delayed graft function (DGF), defined as the need for dialysis within the first 7 days post-transplantation excluding the first day post-transplantation * efficacy failure (biopsy proven acute rejection (BPAR), graft loss, death or loss to follow-up) * wound healing disorder related to initial transplant surgery
Time frame: at 12 Month post-transplantation
Population: Intention to treat (ITT) population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 12 Months Post-transplantation. | Efficacy failure (Total) | 22 Participants |
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 12 Months Post-transplantation. | Failure at month 12 - Total | 42 Participants |
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 12 Months Post-transplantation. | --Graft Loss | 6 Participants |
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 12 Months Post-transplantation. | --Lost to follow-up (composite efficacy endpoint) | 0 Participants |
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 12 Months Post-transplantation. | --BPAR | 13 Participants |
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 12 Months Post-transplantation. | Wound healing disorder | 26 Participants |
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 12 Months Post-transplantation. | --Death | 5 Participants |
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 12 Months Post-transplantation. | Loss to follow-up for the primary failure endpoint | 0 Participants |
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 12 Months Post-transplantation. | Dialysis within first 7 days | 16 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 12 Months Post-transplantation. | Loss to follow-up for the primary failure endpoint | 3 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 12 Months Post-transplantation. | Dialysis within first 7 days | 18 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 12 Months Post-transplantation. | Efficacy failure (Total) | 25 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 12 Months Post-transplantation. | --BPAR | 15 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 12 Months Post-transplantation. | --Graft Loss | 5 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 12 Months Post-transplantation. | --Death | 2 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 12 Months Post-transplantation. | Failure at month 12 - Total | 49 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 12 Months Post-transplantation. | --Lost to follow-up (composite efficacy endpoint) | 5 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 12 Months Post-transplantation. | Wound healing disorder | 28 Participants |
Secondary
Number of Participants Considered in Failure for the Primary Failure Endpoint at 6 Months Post-transplantation.
The primary efficacy variable was the primary failure endpoint at 6 months defined as the occurrence of one or more of the following events within the first 6 months: * delayed graft function (DGF), defined as the need for dialysis within the first 7 days post-transplantation excluding the first day post-transplantation * efficacy failure (biopsy proven acute rejection (BPAR), graft loss, death or loss to follow-up) * wound healing disorder related to initial transplant surgery
Time frame: at 6 Month post-transplantation
Population: Intention to treat (ITT) population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 6 Months Post-transplantation. | --BPAR | 10 Participants |
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 6 Months Post-transplantation. | Failure at month 6 - Total | 39 Participants |
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 6 Months Post-transplantation. | --Death | 4 Participants |
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 6 Months Post-transplantation. | --Lost to follow-up (composite efficacy endpoint) | 0 Participants |
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 6 Months Post-transplantation. | --Graft Loss | 5 Participants |
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 6 Months Post-transplantation. | Wound healing disorder | 25 Participants |
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 6 Months Post-transplantation. | Dialysis within first 7 days | 16 Participants |
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 6 Months Post-transplantation. | Loss to follow-up for the primary failure endpoint | 0 Participants |
| Immediate Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 6 Months Post-transplantation. | Efficacy failure (Total) | 17 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 6 Months Post-transplantation. | Loss to follow-up for the primary failure endpoint | 3 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 6 Months Post-transplantation. | Efficacy failure (Total) | 22 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 6 Months Post-transplantation. | --BPAR | 13 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 6 Months Post-transplantation. | --Death | 2 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 6 Months Post-transplantation. | Failure at month 6 - Total | 48 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 6 Months Post-transplantation. | Dialysis within first 7 days | 18 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 6 Months Post-transplantation. | --Graft Loss | 4 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 6 Months Post-transplantation. | --Lost to follow-up (composite efficacy endpoint) | 4 Participants |
| Delayed Everolimus | Number of Participants Considered in Failure for the Primary Failure Endpoint at 6 Months Post-transplantation. | Wound healing disorder | 28 Participants |
Secondary
Number of Participants Who Underwent Any Dialysis Within the 12-month Treatment Period
The number of patients who underwent any dialysis within the 12-month treatment period.
Time frame: Month 12
Population: Intention to treat (ITT) population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Immediate Everolimus | Number of Participants Who Underwent Any Dialysis Within the 12-month Treatment Period | 16 Participants |
| Delayed Everolimus | Number of Participants Who Underwent Any Dialysis Within the 12-month Treatment Period | 24 Participants |
Secondary
Number of Participants With Any Wound Healing Disorder During the 12-month Treatment Period
A wound was considered healed if all the suture material and staples were removed and the wound was intact by 3 weeks. Any wound opened beyond this point, infected, drained fluid or herniated was considered not healed.
Time frame: Month 12
Population: Intention to treat (ITT) population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Immediate Everolimus | Number of Participants With Any Wound Healing Disorder During the 12-month Treatment Period | Any wound healing disorder -Total | 28 Participants |
| Immediate Everolimus | Number of Participants With Any Wound Healing Disorder During the 12-month Treatment Period | Wound healing disorder related to transplant | 26 Participants |
| Immediate Everolimus | Number of Participants With Any Wound Healing Disorder During the 12-month Treatment Period | Wound healing disorder unrelated to transplant | 2 Participants |
| Delayed Everolimus | Number of Participants With Any Wound Healing Disorder During the 12-month Treatment Period | Any wound healing disorder -Total | 32 Participants |
| Delayed Everolimus | Number of Participants With Any Wound Healing Disorder During the 12-month Treatment Period | Wound healing disorder related to transplant | 28 Participants |
| Delayed Everolimus | Number of Participants With Any Wound Healing Disorder During the 12-month Treatment Period | Wound healing disorder unrelated to transplant | 6 Participants |