Renal Transplantation
Conditions
Brief summary
This study wants to address whether a calcineurin-inhibitor (CNI)-free regimen six weeks after transplantation for Eurotransplant Senior Program (ESP) patients is as safe and well tolerated as standard treatment but optimizing immunosuppressive therapy with benefits in renal function, new-onset diabetes mellitus, cardiovascular risk, cancer and allograft nephropathy.
Interventions
DRUGBasiliximab
On day 0, 2 hours prior to transplant and day 4 post-transplant, 20 mg x2 were given to all participants. Post randomization, 20mg at weeks 7 and 12 were given to the Everolimus group.
DRUGEnteric Coated Mycophenolic Acid (MPA)
A loading dose regimen of 2880 mg/day during weeks 1 and 2 (pre-randomization) were given. During weeks 3 - 6 (pre-randomization), 2160 mg/day were given and during weeks 7 - 24, 1440 mg/day were given if tolerated. Dose reductions due to side effects were possible.
DRUGRAD001
Upon randomization, 3 mg (od) on Day 1, and 3 mg (1.5 mg every 12 hours) on Day 2 was given. Afterwards, the dosage was based on blood trough level (5 - 10 ng/mL).
Dosage was based according to blood level
DRUGCorticosteroids
Dosage was administered according to local standards and administration was optional as per clinical need and the Investigators' discretion. Steroid withdrawal occurred after week 2 (pre-randomization).
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
65 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients receiving a primary kidney from a donor aged \> 65 years * In the Eurotransplant Senior Program * Recipients of de novo cadaveric kidney transplants
Exclusion criteria
* Multi-organ recipients (e.g., kidney and pancreas) * Patients receiving a kidney from a non-heart beating donor * Patients who are recipients of A-B-O incompatible transplants * Patients with already existing antibodies against the HLA-type of the receiving transplant * Patients who have received an investigational immunosuppressive drug within four weeks prior to study entry (Baseline visit 1) * Patients with thrombocytopenia, with an absolute neutrophil count of \< 1,500/mm³ or leucopenia or hemoglobin \< 6 g/dL * Patients who are HIV, HCV RNA, or Hepatitis B surface antigen positive * Evidence of severe liver disease * Females at randomization who will be not considered post-menopausal Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Renal Function by Glomerular Filtration Rate (GFR) Via Cockcroft-Gault Method | Month 6 | The study was terminated prematurely and not powered for efficacy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Renal Function by Serum Creatinine | Months 6, 12, 24, 36, 48 and 60 | The study was terminated prematurely and not powered for efficacy. |
| Biopsy Proven Acute Rejection (BPAR), Graft Loss and Death | Months 6, 12, 24, 36, 48 and 60 | The study was terminated prematurely and not powered for efficacy. |
| Occurrence of Treatment Failures | Month 6 | The study was terminated prematurely and not powered for efficacy. |
| Evolution of Renal Function (Creatinine Slope) | Week 7, Month 6 | The study was terminated prematurely and not powered for efficacy. |
| Renal Function by GFR Via Modification of Diet in Renal Diseases (MDRD) and Nankivell Method | Month 6 | The study was terminated prematurely and not powered for efficacy. |
| Number of Participants Who Experienced Adverse Events, Serious Adverse Events and Death | Months 6, 12, 24, 36, 48 and 60 | Participants with adverse events (serious plus non-serious), serious adverse events and death were reported. |
| Renal Function by GFR Over Time | Months 12, 24, 36, 48 and 60 | — |
| Renal Function by Proteinuria | Months12, 24, 36, 48 and 60 | — |
| CD25 Saturation on Lymphocytes | Month 6 | — |
Countries
Germany
Participant flow
Recruitment details
The study consisted of a main period and a 54 month observation follow-up period. The main period included a pre-randomized treatment phase (6 weeks) and a randomized treatment phase (18 weeks). All randomized participants, who participated in the main period, were eligible for the follow-up period.
Pre-assignment details
At baseline (BL) 1 (pre-randomization), eligible participants received a CNI-based regimen for 6 weeks. At BL2 (randomization), eligible participants were randomized in a 1:2 ratio to the control group or everolimus group.
Participants by arm
| Arm | Count |
|---|---|
| Control Group During the pre-randomized treatment phase, all participants received a CNI-based regimen consisting of basiliximab, mycophenolic acid (MPA), cyclosporin A (CsA) and corticosteroids (optional). Upon randomization, participants in this group continued with a CNI-based regimen of MPA and CsA. | 24 |
| Everolimus Group During the pre-randomized treatment phase, all participants received a CNI-based regimen consisting of basiliximab, mycophenolic acid (MPA), cyclosporin A (CsA) and corticosteroids (optional). Upon randomization, participants in this group made a stepwise switch to a CNI-free regimen of everolimus and MPA. | 51 |
| Total | 75 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Follow-up Period | Follow-up period was terminated. | 20 | 32 | 0 |
| Main Period (Pre-randomization) | Abnormal laboratory value | 0 | 0 | 44 |
| Main Period (Pre-randomization) | Abnormal test procedure result | 0 | 0 | 2 |
| Main Period (Pre-randomization) | Administrative problems | 0 | 0 | 6 |
| Main Period (Pre-randomization) | Adverse Event | 0 | 0 | 36 |
| Main Period (Pre-randomization) | Death | 0 | 0 | 1 |
| Main Period (Pre-randomization) | Graft loss | 0 | 0 | 7 |
| Main Period (Pre-randomization) | Lack of Efficacy | 0 | 0 | 20 |
| Main Period (Pre-randomization) | Not specified (data missing) | 0 | 0 | 1 |
| Main Period (Pre-randomization) | Protocol Violation | 0 | 0 | 1 |
| Main Period (Pre-randomization) | Withdrawal by Subject | 0 | 0 | 12 |
| Main Period (Randomization) | Abnormal laboratory value | 0 | 2 | 0 |
| Main Period (Randomization) | Adverse Event | 0 | 15 | 0 |
| Main Period (Randomization) | Lack of Efficacy | 1 | 10 | 0 |
Baseline characteristics
| Characteristic | Control Group | Everolimus Group | Total |
|---|---|---|---|
| Age, Continuous | 69.3 Years STANDARD_DEVIATION 3.1 | 68.4 Years STANDARD_DEVIATION 3.3 | 68.7 Years STANDARD_DEVIATION 3.3 |
| Sex: Female, Male Female | 8 Participants | 26 Participants | 34 Participants |
| Sex: Female, Male Male | 16 Participants | 25 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 24 | 50 / 51 |
| serious Total, serious adverse events | 11 / 24 | 28 / 51 |
Outcome results
Primary
Renal Function by Glomerular Filtration Rate (GFR) Via Cockcroft-Gault Method
The study was terminated prematurely and not powered for efficacy.
Time frame: Month 6
Population: This outcome measure was not analyzed because a total of 244 completed subjects were needed to have a power of 80% in detecting a significant difference between treatment groups. Due to early termination, the study was limited by a small sample size; hence, the planned analysis was not done.
Secondary
Biopsy Proven Acute Rejection (BPAR), Graft Loss and Death
The study was terminated prematurely and not powered for efficacy.
Time frame: Months 6, 12, 24, 36, 48 and 60
Population: This outcome measure was not analyzed because a total of 244 completed subjects were needed to have a power of 80% in detecting a significant difference between treatment groups. Due to early termination, the study was limited by a small sample size; hence, the planned analysis was not done.
Secondary
CD25 Saturation on Lymphocytes
Time frame: Month 6
Population: This outcome measure was not analyzed because a total of 244 completed subjects were needed to have a power of 80% in detecting a significant difference between treatment groups. Due to early termination, the study was limited by a small sample size; hence, the planned analysis was not done.
Secondary
Evolution of Renal Function (Creatinine Slope)
The study was terminated prematurely and not powered for efficacy.
Time frame: Week 7, Month 6
Population: This outcome measure was not analyzed because a total of 244 completed subjects were needed to have a power of 80% in detecting a significant difference between treatment groups. Due to early termination, the study was limited by a small sample size; hence, the planned analysis was not done.
Secondary
Number of Participants Who Experienced Adverse Events, Serious Adverse Events and Death
Participants with adverse events (serious plus non-serious), serious adverse events and death were reported.
Time frame: Months 6, 12, 24, 36, 48 and 60
Population: Randomized Safety Set: This set included all randomized participants who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Control Group | Number of Participants Who Experienced Adverse Events, Serious Adverse Events and Death | Adverse events (serious and non-serious) | 21 Participants |
| Control Group | Number of Participants Who Experienced Adverse Events, Serious Adverse Events and Death | Serious adverse events | 11 Participants |
| Control Group | Number of Participants Who Experienced Adverse Events, Serious Adverse Events and Death | Deaths | 0 Participants |
| Everolimus Group | Number of Participants Who Experienced Adverse Events, Serious Adverse Events and Death | Adverse events (serious and non-serious) | 50 Participants |
| Everolimus Group | Number of Participants Who Experienced Adverse Events, Serious Adverse Events and Death | Serious adverse events | 28 Participants |
| Everolimus Group | Number of Participants Who Experienced Adverse Events, Serious Adverse Events and Death | Deaths | 0 Participants |
Secondary
Occurrence of Treatment Failures
The study was terminated prematurely and not powered for efficacy.
Time frame: Month 6
Population: This outcome measure was not analyzed because a total of 244 completed subjects were needed to have a power of 80% in detecting a significant difference between treatment groups. Due to early termination, the study was limited by a small sample size; hence, the planned analysis was not done.
Secondary
Renal Function by GFR Over Time
Time frame: Months 12, 24, 36, 48 and 60
Population: This outcome measure was not analyzed because a total of 244 completed subjects were needed to have a power of 80% in detecting a significant difference between treatment groups. Due to early termination, the study was limited by a small sample size; hence, the planned analysis was not done.
Secondary
Renal Function by GFR Via Modification of Diet in Renal Diseases (MDRD) and Nankivell Method
The study was terminated prematurely and not powered for efficacy.
Time frame: Month 6
Population: This outcome measure was not analyzed because a total of 244 completed subjects were needed to have a power of 80% in detecting a significant difference between treatment groups. Due to early termination, the study was limited by a small sample size; hence, the planned analysis was not done.
Secondary
Renal Function by Proteinuria
Time frame: Months12, 24, 36, 48 and 60
Population: This outcome measure was not analyzed because a total of 244 completed subjects were needed to have a power of 80% in detecting a significant difference between treatment groups. Due to early termination, the study was limited by a small sample size; hence, the planned analysis was not done.
Secondary
Renal Function by Serum Creatinine
The study was terminated prematurely and not powered for efficacy.
Time frame: Months 6, 12, 24, 36, 48 and 60
Population: This outcome measure was not analyzed because a total of 244 completed subjects were needed to have a power of 80% in detecting a significant difference between treatment groups. Due to early termination, the study was limited by a small sample size; hence, the planned analysis was not done.