Liver Transplantation
Conditions
Keywords
Liver transplantation, everolimus, CNI
Brief summary
The study is designed to show that everolimus initiation together with reduction and thereafter discontinuation of calcineurin inhibitor (CNI) will improve significantly renal function in de novo liver transplant recipients as compared to continuation of CNI-based treatment.
Interventions
DRUGeverolimus
Start dose of everolimus was 1.5 mg in the morning followed by 1.5 mg in the evening. After one week, the dose was adjusted to achieve trough levels between 5-12 ng/mL. Once trough levels were above 5ng/mL, the CNI dose was reduced to 70%. At week 8 post-baseline (latest at week 16 post baseline), CNI was completely discontinued. For patients receiving Ciclosporin A (CiA) as CNI, the everolimus dosage was adjusted to achieve a trough level of 8-12 ng/mL, prior to discontinuation of CiA. After discontinuation of CNI, everolimus was maintained at a trough level of 5-12 ng/mL.
DRUGbasiliximab
All patients who met the eligibility criteria were treated with 2 doses of basiliximab on Day 0 (transplantation) and Day 4.
DRUGCNI
Patients who met the screening eligibility received CNI-based immunosuppressive therapy for 1 month. Then at week 4 (or week 8 at maximum), patients randomized to the CNI arm continued on CNI-based immunosuppressive therapy.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Males or females 18 - 70 years old * Liver transplant recipient (living or deceased donor) * Patients in whom an allograft biopsy will not be contraindicated
Exclusion criteria
* Recipients of multiple solid organ transplants or patients that have already received a transplant in the past * HCV positive patients who need an active anti-viral treatment (HCV- positive patients without active antiviral treatment are allowed) * HIV positive patients * Patients who are breast feeding * Patients with a current severe systemic infection * Presence of any hypersensitivity to drugs similar to Certican® (e.g. macrolides) * Preexisting (i.e. not related to CNI-damage) renal dysfunction that, according to the judgment of the investigator, will not significantly improve after transplantation (i.e., for example, patients that are expected to have a cGFR below 50ml/min at 4 weeks post transplantation) * Patients that have received Simulect prior to this study. * Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Calculated Glomerular Filtration Rate (cGFR) | Month 11 | This outcome measure evaluated renal function by assessing the calculated GFR based on the Cockcroft-Gault formula. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of the Need for a Change in the Immunosuppressive Regimen | Month 11 | The incidence of any changes in the immunosuppressive regimen other than allowed in the study protocol (for example, introduction of Mycophenolic acid (MPA) or sirolimus) was estimated using crude rate estimation (relative frequency). |
| Incidence of Renal Deterioration | Baseline, Month 11 | Renal deterioration was defined as a decrease by ≥25% in the cGFR compared to baseline and confirmed by one consecutive measurement. The analysis of this outcome measure was omitted because of missing relevance. |
| Renal Function (cGFR) | Month 5 | This outcome measure evaluated renal function by assessing the calculated GFR based on the Cockcroft-Gault formula. |
| Incidence of Efficacy Failure | Month 11 | Efficacy failure was defined as the composite endpoint of biopsy-proven acute rejection (BPAR), graft loss, death, lost to follow-up (from any reason), whichever occurred first. Incidence of efficacy failure was estimated using crude rate estimation (relative frequency). |
| Patient and Graft Survival | Month 11 | Patient survival was defined as the time from date of randomization to date of death from any cause. If a patient was not known to have died, patient survival was censored as the date of last contact. Graft survival was defined as the time from the date of randomization to the date of graft loss. If a patient was not known to suffer from a graft loss or died without graft loss, time to graft loss was censored with date of last contact or date of death, respectively. Patient and graft survival were analyzed using the Kaplan Meier method. |
| Hepatitis C Virus (HCV) Replication in HCV-positive Patients | Baseline, Month 5 | HCV ribonucleic acid (RNA) was measured by real time reverse transcriptase polymerase chain reaction (PCR; copies per mL). |
| Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death | From randomization to Month 11 | Patients with all (serious and non-serious) adverse events, serious adverse events and death were reported. |
| Incidence of Treated BPAR | Month 11 | The incidence of treated BPAR was estimated using crude rate estimation (relative frequency). |
Countries
Austria, Germany, Netherlands, Switzerland
Participant flow
Recruitment details
The core study consisted of 2 periods: 1) during the first one-month period, 276 eligible participants received the same CNI-based immunosuppressive therapy prior to randomization; 2) during the second 11-month study period, 203 participants eligible participants were randomized in a 1:1 ratio to one of the two treatment arms.
Participants by arm
| Arm | Count |
|---|---|
| Everolimus Basiliximab plus everolimus-based immunosuppressive regimen following the reduction and cessation of initial CNI regimen plus optional steroids according to local best practice | 96 |
| Calcineurin Inhibitor (CNI) Basiliximab plus CNI-based immunosuppressive regimen according to local best practice plus optional steroids according to local best practice | 98 |
| Total | 194 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Core (Randomization to Month 11) | Administrative Problems | 2 | 2 |
| Core (Randomization to Month 11) | Adverse Event | 1 | 0 |
| Core (Randomization to Month 11) | Death | 5 | 3 |
| Core (Randomization to Month 11) | Graft loss | 1 | 2 |
| Core (Randomization to Month 11) | Lack of Efficacy | 0 | 1 |
| Core (Randomization to Month 11) | Lost to Follow-up | 0 | 1 |
| Core (Randomization to Month 11) | Protocol deviation | 0 | 1 |
| Core (Randomization to Month 11) | Withdrawal by Subject | 5 | 2 |
| Extension (Month 12 to Month 59) | Administrative problems | 1 | 0 |
| Extension (Month 12 to Month 59) | Adverse Event | 8 | 7 |
| Extension (Month 12 to Month 59) | Death | 1 | 2 |
| Extension (Month 12 to Month 59) | Lack of Efficacy | 3 | 1 |
| Extension (Month 12 to Month 59) | Lost to Follow-up | 1 | 1 |
| Extension (Month 12 to Month 59) | Withdrawal by Subject | 0 | 3 |
Baseline characteristics
| Characteristic | Everolimus | Calcineurin Inhibitor (CNI) | Total |
|---|---|---|---|
| Age, Continuous | 52.3 Years STANDARD_DEVIATION 9.9 | 52.9 Years STANDARD_DEVIATION 10.1 | 52.6 Years STANDARD_DEVIATION 1 |
| Sex: Female, Male Female | 42 Participants | 30 Participants | 72 Participants |
| Sex: Female, Male Male | 54 Participants | 68 Participants | 122 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 92 / 101 | 87 / 102 | 39 / 41 | 38 / 40 |
| serious Total, serious adverse events | 67 / 101 | 58 / 102 | 26 / 41 | 28 / 40 |
Outcome results
Primary
Calculated Glomerular Filtration Rate (cGFR)
This outcome measure evaluated renal function by assessing the calculated GFR based on the Cockcroft-Gault formula.
Time frame: Month 11
Population: ITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Everolimus | Calculated Glomerular Filtration Rate (cGFR) | 87.9 mL/min | Standard Deviation 32 |
| Calcineurin Inhibitor (CNI) | Calculated Glomerular Filtration Rate (cGFR) | 84.1 mL/min | Standard Deviation 34.9 |
Secondary
Hepatitis C Virus (HCV) Replication in HCV-positive Patients
HCV ribonucleic acid (RNA) was measured by real time reverse transcriptase polymerase chain reaction (PCR; copies per mL).
Time frame: Baseline, Month 5
Population: ITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Everolimus | Hepatitis C Virus (HCV) Replication in HCV-positive Patients | Baseline, negative | 64.5 Percentage of participants |
| Everolimus | Hepatitis C Virus (HCV) Replication in HCV-positive Patients | Baseline, positive | 0.0 Percentage of participants |
| Everolimus | Hepatitis C Virus (HCV) Replication in HCV-positive Patients | Baseline, not done | 35.5 Percentage of participants |
| Everolimus | Hepatitis C Virus (HCV) Replication in HCV-positive Patients | Month 5, negative | 62.9 Percentage of participants |
| Everolimus | Hepatitis C Virus (HCV) Replication in HCV-positive Patients | Month 5, positive | 1.6 Percentage of participants |
| Everolimus | Hepatitis C Virus (HCV) Replication in HCV-positive Patients | Month 5, not done | 35.5 Percentage of participants |
| Calcineurin Inhibitor (CNI) | Hepatitis C Virus (HCV) Replication in HCV-positive Patients | Month 5, positive | 13.2 Percentage of participants |
| Calcineurin Inhibitor (CNI) | Hepatitis C Virus (HCV) Replication in HCV-positive Patients | Baseline, negative | 55.3 Percentage of participants |
| Calcineurin Inhibitor (CNI) | Hepatitis C Virus (HCV) Replication in HCV-positive Patients | Month 5, negative | 38.2 Percentage of participants |
| Calcineurin Inhibitor (CNI) | Hepatitis C Virus (HCV) Replication in HCV-positive Patients | Baseline, positive | 0.0 Percentage of participants |
| Calcineurin Inhibitor (CNI) | Hepatitis C Virus (HCV) Replication in HCV-positive Patients | Month 5, not done | 48.7 Percentage of participants |
| Calcineurin Inhibitor (CNI) | Hepatitis C Virus (HCV) Replication in HCV-positive Patients | Baseline, not done | 44.7 Percentage of participants |
Secondary
Incidence of Efficacy Failure
Efficacy failure was defined as the composite endpoint of biopsy-proven acute rejection (BPAR), graft loss, death, lost to follow-up (from any reason), whichever occurred first. Incidence of efficacy failure was estimated using crude rate estimation (relative frequency).
Time frame: Month 11
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus | Incidence of Efficacy Failure | 20.8 Percentage of participants |
| Calcineurin Inhibitor (CNI) | Incidence of Efficacy Failure | 20.4 Percentage of participants |
Secondary
Incidence of Renal Deterioration
Renal deterioration was defined as a decrease by ≥25% in the cGFR compared to baseline and confirmed by one consecutive measurement. The analysis of this outcome measure was omitted because of missing relevance.
Time frame: Baseline, Month 11
Secondary
Incidence of the Need for a Change in the Immunosuppressive Regimen
The incidence of any changes in the immunosuppressive regimen other than allowed in the study protocol (for example, introduction of Mycophenolic acid (MPA) or sirolimus) was estimated using crude rate estimation (relative frequency).
Time frame: Month 11
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus | Incidence of the Need for a Change in the Immunosuppressive Regimen | 80.2 Percentage of participants |
| Calcineurin Inhibitor (CNI) | Incidence of the Need for a Change in the Immunosuppressive Regimen | 73.5 Percentage of participants |
Secondary
Incidence of Treated BPAR
The incidence of treated BPAR was estimated using crude rate estimation (relative frequency).
Time frame: Month 11
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Everolimus | Incidence of Treated BPAR | 13.5 Percentage of Participants |
| Calcineurin Inhibitor (CNI) | Incidence of Treated BPAR | 10.2 Percentage of Participants |
Secondary
Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death
Patients with all (serious and non-serious) adverse events, serious adverse events and death were reported.
Time frame: From randomization to Month 11
Population: Safety population: This set included all randomized patients with at least one post-baseline measurement of GFR.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Everolimus | Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death | Deaths | 4 Number of participants |
| Everolimus | Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death | Adverse Events (serious and non-serious) | 98 Number of participants |
| Everolimus | Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death | Serious Adverse Events | 67 Number of participants |
| Calcineurin Inhibitor (CNI) | Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death | Deaths | 4 Number of participants |
| Calcineurin Inhibitor (CNI) | Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death | Adverse Events (serious and non-serious) | 96 Number of participants |
| Calcineurin Inhibitor (CNI) | Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death | Serious Adverse Events | 58 Number of participants |
Secondary
Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death
Patients with all (serious and non-serious) adverse events, serious adverse events and death were reported.
Time frame: Month 12 to Month 59 post-baseline
Population: Safety population: This set included all randomized patients with at least one post-baseline measurement of GFR.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Everolimus | Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death | Adverse Events (serious and non-serious) | 41 Number of participants |
| Everolimus | Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death | Serious Adverse Events | 26 Number of participants |
| Everolimus | Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death | Deaths | 1 Number of participants |
| Calcineurin Inhibitor (CNI) | Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death | Adverse Events (serious and non-serious) | 40 Number of participants |
| Calcineurin Inhibitor (CNI) | Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death | Serious Adverse Events | 28 Number of participants |
| Calcineurin Inhibitor (CNI) | Number of Patients Who Experienced Adverse Events, Serious Adverse Events and Death | Deaths | 2 Number of participants |
Secondary
Patient and Graft Survival
Patient survival was defined as the time from date of randomization to date of death from any cause. If a patient was not known to have died, patient survival was censored as the date of last contact. Graft survival was defined as the time from the date of randomization to the date of graft loss. If a patient was not known to suffer from a graft loss or died without graft loss, time to graft loss was censored with date of last contact or date of death, respectively. Patient and graft survival were analyzed using the Kaplan Meier method.
Time frame: Month 11
Population: ITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Everolimus | Patient and Graft Survival | Death | 4.3 Percentage of Participants |
| Everolimus | Patient and Graft Survival | Graft loss | 2.2 Percentage of Participants |
| Calcineurin Inhibitor (CNI) | Patient and Graft Survival | Death | 4.1 Percentage of Participants |
| Calcineurin Inhibitor (CNI) | Patient and Graft Survival | Graft loss | 2.1 Percentage of Participants |
Secondary
Renal Function (cGFR)
This outcome measure evaluated renal function by assessing the calculated GFR based on the Cockcroft-Gault formula.
Time frame: Month 5
Population: ITT
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Everolimus | Renal Function (cGFR) | 88.7 mL/min | Standard Deviation 31 |
| Calcineurin Inhibitor (CNI) | Renal Function (cGFR) | 82.9 mL/min | Standard Deviation 29.4 |