Kidney Transplantation
Conditions
Keywords
Everolimus, mycophenolate, CNI-free, kidney transplantation
Brief summary
The purpose of this study is to compare renal function of immunosuppressive regimens with different relevance of the calcineurin inhibitor (CNI) cyclosporine: standard dose CNI, low dose CNI, CNI free in de novo kidney transplant patients after 12 months of therapy.
Interventions
DRUGEverolimus
Tablet containing 0.5 mg or 0.75 mg. Dosing schedule: Initially 1.5 mg/day, then based on blood level (5-10 ng/mL in CNI free, 3-8 ng/mL in CNI low regimen
DRUGMyfortic
1 tablet containing 180 mg or 360 mg Dosing schedule: Initially 1.5 mg/day, then based on blood level (5-10 ng/mL in CNI free, 3-8 ng/mL in CNI low regimen) According to blood level 1440 mg/day (2 x 720 mg), if tolerated. Dose reduction possible in case of side effects (min. dose at BL2 (Month 3): 720 mg/day)
DRUGSandimmun Optoral
1 capsule containing 10, 25, 50, or 100mg. Dosing: According to blood level
DRUGSimulect®
Lyophilisate in vials with ampoules of sterile water for injection (5 ml). Dosing: 1 vial containing 20 mg lyophilisate. Dosing schedule: 2 x 20 mg to be applied as 10 sec. bolus injection, i.v. on Day 0 (2 h before transplant) and on Day 4
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, aged 18 - 70 years * Recipients of de novo cadaveric, living unrelated or living related kidney transplants * Females capable of becoming pregnant must have a negative serum pregnancy test within 7 days prior to or at screening, 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. * Patients who are willing and able to participate in the study and from whom written informed consent has been obtained.
Exclusion criteria
* More than one previous renal transplantation * Multi-organ recipients (e.g., kidney and pancreas) or previous transplant with any other organ, different from kidney * Patients receiving a kidney from a non-heart beating donor * Donor age: \< 5 years or \> 70 years * Graft loss due to immunological reasons in the first year after transplantation (in case of secondary transplantation) * Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| GFR Via Nankivell Method at Month 12 - CNI-Free vs Standard Regimen | From randomization at BL2 (Month 3) to Month 12 post-transplant | Demonstrate superiority of CNI-Free vs Standard Regimen in GFR using the Nankivell formula (GFR = 6.7 / Scr + BW / 4 - Surea / 2-100 / (height)² + C where where Scr is the serum creatinine concentration expressed in mmol/L, BW the body weight in kilograms, Surea the serum urea in mmol/L, height in m, and the constant C is 35 for male and 25 for female patients. The calculated GFR is expressed in mL/min per 1.73m², last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model, with treatment, center, donor type (deceased vs. living) as factors and BL2-value at V4/M3/BL2 as covariate. P-values are not adjusted |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| GFR at Month 12 Utilizing Modification of Diet in Renal Disease (MDRD) Method | From randomization at BL2 (Month 3) to Month 12 post-transplant | Change in GFR (Modification of Diet in Renal Disease calculated using the -MDRD formulat: For men: GFR = 170 × (serum creatinine -0,999)×(age-0,176) x (urea nitrogen -0,17) × (albumin0,318) For women: GFR = 170 × (serum creatinine -0,999) × (age-0,176) × (urea nitrogen -0,17) x (albumin0,318) × 0.762 with urea nitrogen = urea / 2.144. ), last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model, with treatment, center, donor type (deceased vs. living) as factors and BL2-value at V4/M3/BL2 as covariate. |
| GFR at Month 12 Utilizing Cockcroft-Gault Formula | From randomization at BL2 (Month 3) to Month 12 post-transplant | Cockcroft-Gault formula: For men: GFR= ((140-age) × body weight in kg)∕(72 x serum creatinine in mg∕dl)For women: GFR= (0.85×(140-age) × body weight in kg)∕(72 x serum creatinine in mg/dl), ), last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model |
| Mean Change in Serum Creatinine From Month 3 to Month 12 | From randomization at BL2 (Month 3) to Month 12 post-transplant | Change in venous blood serum creatinine. Last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model |
| Efficacy Event Data From Baseline 2 (Month 3) to Month 6 | From Baseline 2 (Month 3) to Month 6 | Efficacy events were: Biopsy-proven acute rejection (BPAR), graft loss, death, and treatment failure (defined as composite endpoint of BPAR, graft loss, death, loss to follow-up, discontinuation due to lack of efficacy or due to toxicity). |
| Efficacy Event Data Baseline 2 (Month 3) to Month 12 | From Baseline 2 (Month 3) to Month 12 | Efficacy events were: Biopsy-proven acute rejection (BPAR), graft loss, death, and treatment failure (defined as composite endpoint of BPAR, graft loss, death, loss to follow-up, discontinuation due to lack of efficacy or due to toxicity). |
| GFR Via Nankivell Formula at Month 12 - All Regimens | From randomization at BL2 (Month 3) to Month 12 post-transplant | Change in GFR using the Nankivell formula (GFR = 6.7 / Scr + BW / 4 - Surea / 2-100 / (height)² + C where where Scr is the serum creatinine concentration expressed in mmol/L, BW the body weight in kilograms, Surea the serum urea in mmol/L, height in m, and the constant C is 35 for male and 25 for female patients. The calculated GFR is expressed in mL/min per 1.73m², last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model, with treatment, center, donor type (deceased vs. living) as factors and BL2-value at V4/M3/BL2 as covariate. |
| GFR Calculated Via Nankivell Formula at Month 60 | From randomization at BL2 (Month 3) to Month 60 | Change in GFR using the Nankivell formula (GFR = 6.7 / Scr + BW / 4 - Surea / 2-100 / (height)² + C where where Scr is the serum creatinine concentration expressed in mmol/L, BW the body weight in kilograms, Surea the serum urea in mmol/L, height in m, and the constant C is 35 for male and 25 for female patients. The calculated GFR is expressed in mL/min per 1.73m², last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model, with treatment, center, donor type (deceased vs. living) as factors and BL2-value at V4/M3/BL2 as covariate. |
| GFR at Month 60 Utilizing Cockcroft-Gault Formula | From randomization at BL2 (Month 3) to Month 60 post-transplant | Cockcroft-Gault formula: For men: GFR= ((140-age) × body weight in kg)∕(72 x serum creatinine in mg∕dl) For women: GFR= (0.85×(140-age) × body weight in kg)∕(72 x serum creatinine in mg/dl), ), last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model |
| GFR at Month 60 Utilizing Modification of Diet in Renal Disease (MDRD) Method | From randomization at BL2 (Month 3) to Month 60 post-transplant | Change in GFR (Modification of Diet in Renal Disease calculated using the -MDRD formulat: For men: GFR = 170 × (serum creatinine -0,999)×(age-0,176) x (urea nitrogen -0,17) × (albumin0,318) For women: GFR = 170 × (serum creatinine -0,999) × (age-0,176) × (urea nitrogen -0,17) x (albumin0,318) × 0.762 with urea nitrogen = urea / 2.144. ), last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model, with treatment, center, donor type (deceased vs. living) as factors and BL2-value at V4/M3/BL2 as covariate. |
| Mean Change in Serum Creatinine From Month 3 to Month 60 | From randomization at BL2 (Month 3) to Month 60 post-transplant | Change in venous blood serum creatinine. Last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model |
| Efficacy Event Data After Month 12 to Month 60 | Events starting after Month 12 | Efficacy events were: Biopsy-proven acute rejection (BPAR), graft loss, death, and treatment failure (defined as composite endpoint of BPAR, graft loss, death, loss to follow-up, discontinuation due to lack of efficacy or due to toxicity). |
| Change From BL2 (Month 3) to Month 12 in Cardiovascular Risk (Framingham Score; 10-year Cardiovascular Risk) | From Baseline 2 (Month 3) to Month 12 | The Framingham Score (based on LDL cholesterol level) estimates the coronary heart disease risk (%) of developing one of the following coronary heart diseases: angina pectoris, myocardial infarction, or coronary disease death, over the course of 10 years. |
Countries
Germany, Switzerland
Participant flow
Recruitment details
.817 patients were screened and 802 were enrolled on Day of transplant which served as Baseline Visit 1. For three months post transplantation, in the pre-phase period, all patients received induction therapy (Simulect®) and immunosuppressive therapy consisting of Myfortic, Sandimmun Optoral and corticosteroids.
Pre-assignment details
At month 3 post transplant, Baseline Visit 2, additional eligibility was assessed and patients randomized to one of 3 treatment arms and stratified according to kidney donor (living or cadaveric).
Participants by arm
| Arm | Count |
|---|---|
| Standard Regimen Myfortic, Sandimmun Optoral and corticosteroids | 165 |
| CNI Free Regimen CNI free regimen: comprising the following steps for switching treatment:
Step 1 at BL2 + 1 day: Myfortic, everolimus 1.5 mg, Sandimmun Optoral (50% of standard dose) and corticosteroids Step 2 at BL2 + 8 days: Myfortic, everolimus 3 mg and corticosteroids | 171 |
| CNI Low Regimen CNI low regimen: comprising the following steps for switching treatment:
Step 1 at BL2 + 1 day: everolimus 1.5 mg, Sandimmun Optoral and corticosteroids Step 2 at BL2 + 8 days: everolimus 1.5 mg, Sandimmun Optoral (low dose) and corticosteroids | 161 |
| Total | 497 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Extension - 4 Years | Administrative problems | 3 | 1 | 1 |
| Extension - 4 Years | Adverse Event | 9 | 6 | 3 |
| Extension - 4 Years | Death | 8 | 3 | 6 |
| Extension - 4 Years | Lost to Follow-up | 12 | 10 | 9 |
| Extension - 4 Years | Withdrawal by Subject | 5 | 2 | 2 |
| Pre-phase | abnormal lab values | 23 | 0 | 0 |
| Pre-phase | abnormal test procedure results | 15 | 0 | 0 |
| Pre-phase | administrative problems | 2 | 0 | 0 |
| Pre-phase | Adverse Event | 137 | 0 | 0 |
| Pre-phase | condition no longer requires study drug | 7 | 0 | 0 |
| Pre-phase | Death | 10 | 0 | 0 |
| Pre-phase | Lack of Efficacy | 35 | 0 | 0 |
| Pre-phase | Lost to Follow-up | 2 | 0 | 0 |
| Pre-phase | Protocol Violation | 6 | 0 | 0 |
| Pre-phase | Withdrawal by Subject | 66 | 0 | 0 |
| Randomized - 9 Month | Abnormal laboratory values | 0 | 3 | 1 |
| Randomized - 9 Month | Administrative problems | 1 | 1 | 2 |
| Randomized - 9 Month | Adverse Event | 25 | 44 | 27 |
| Randomized - 9 Month | Death | 3 | 2 | 2 |
| Randomized - 9 Month | Lack of Efficacy | 2 | 3 | 1 |
| Randomized - 9 Month | Protocol Violation | 1 | 1 | 0 |
| Randomized - 9 Month | Withdrawal by Subject | 7 | 7 | 5 |
Baseline characteristics
| Characteristic | Total | Standard Regimen | CNI Free Regimen | CNI Low Regimen |
|---|---|---|---|---|
| Age, Continuous | 49.1 years STANDARD_DEVIATION 12.2 | 49.9 years STANDARD_DEVIATION 11.8 | 48.9 years STANDARD_DEVIATION 12.5 | 48.6 years STANDARD_DEVIATION 12.3 |
| Gender Female | 195 Participants | 65 Participants | 69 Participants | 61 Participants |
| Gender Male | 302 Participants | 100 Participants | 102 Participants | 100 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 121 / 165 | 134 / 171 | 133 / 161 |
| serious Total, serious adverse events | 87 / 165 | 91 / 171 | 85 / 161 |
Outcome results
Primary
GFR Via Nankivell Method at Month 12 - CNI-Free vs Standard Regimen
Demonstrate superiority of CNI-Free vs Standard Regimen in GFR using the Nankivell formula (GFR = 6.7 / Scr + BW / 4 - Surea / 2-100 / (height)² + C where where Scr is the serum creatinine concentration expressed in mmol/L, BW the body weight in kilograms, Surea the serum urea in mmol/L, height in m, and the constant C is 35 for male and 25 for female patients. The calculated GFR is expressed in mL/min per 1.73m², last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model, with treatment, center, donor type (deceased vs. living) as factors and BL2-value at V4/M3/BL2 as covariate. P-values are not adjusted
Time frame: From randomization at BL2 (Month 3) to Month 12 post-transplant
Population: Participants analyzed differs due to different input values requested by the different formulas (Nankivell, MDRD and Cockcroft-Gault). ITT Population consisted of all patients who were randomized at Month 3 who received at least one dose of randomized treatment. The ITT population might have included patients without any data after randomization.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Standard Regimen | GFR Via Nankivell Method at Month 12 - CNI-Free vs Standard Regimen | 63.03 ml/min/1.73m² |
| CNI Free Regimen | GFR Via Nankivell Method at Month 12 - CNI-Free vs Standard Regimen | 68.59 ml/min/1.73m² |
| CNI Low Regimen | GFR Via Nankivell Method at Month 12 - CNI-Free vs Standard Regimen | 63.08 ml/min/1.73m² |
p-value: <0.000195% CI: [2.82, 8.31]ANCOVA
Secondary
Change From BL2 (Month 3) to Month 12 in Cardiovascular Risk (Framingham Score; 10-year Cardiovascular Risk)
The Framingham Score (based on LDL cholesterol level) estimates the coronary heart disease risk (%) of developing one of the following coronary heart diseases: angina pectoris, myocardial infarction, or coronary disease death, over the course of 10 years.
Time frame: From Baseline 2 (Month 3) to Month 12
Population: The Intention-to-treat (ITT) Population consisted of all patients who were randomized at BL2 (Month 3), and who received at least one dose of randomized treatment. Patients were analyzed according to their assigned treatment. The ITT population might have included patients without any data after randomization.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Standard Regimen | Change From BL2 (Month 3) to Month 12 in Cardiovascular Risk (Framingham Score; 10-year Cardiovascular Risk) | Baseline 1/Visit 1 (n=165,171,161) | 10.9 Percent risk | Standard Deviation 8 |
| Standard Regimen | Change From BL2 (Month 3) to Month 12 in Cardiovascular Risk (Framingham Score; 10-year Cardiovascular Risk) | Baseline 2/Month 3 (n=165,171,161) | 10.3 Percent risk | Standard Deviation 7.7 |
| Standard Regimen | Change From BL2 (Month 3) to Month 12 in Cardiovascular Risk (Framingham Score; 10-year Cardiovascular Risk) | Month 12 (n=158,166,156) | 9.4 Percent risk | Standard Deviation 6.8 |
| Standard Regimen | Change From BL2 (Month 3) to Month 12 in Cardiovascular Risk (Framingham Score; 10-year Cardiovascular Risk) | Change from Baseline 2 to Month 12 (n=158,166,156) | -0.7 Percent risk | Standard Deviation 5.8 |
| CNI Free Regimen | Change From BL2 (Month 3) to Month 12 in Cardiovascular Risk (Framingham Score; 10-year Cardiovascular Risk) | Change from Baseline 2 to Month 12 (n=158,166,156) | 0.4 Percent risk | Standard Deviation 5.1 |
| CNI Free Regimen | Change From BL2 (Month 3) to Month 12 in Cardiovascular Risk (Framingham Score; 10-year Cardiovascular Risk) | Baseline 1/Visit 1 (n=165,171,161) | 10.2 Percent risk | Standard Deviation 7.4 |
| CNI Free Regimen | Change From BL2 (Month 3) to Month 12 in Cardiovascular Risk (Framingham Score; 10-year Cardiovascular Risk) | Month 12 (n=158,166,156) | 9.1 Percent risk | Standard Deviation 6.4 |
| CNI Free Regimen | Change From BL2 (Month 3) to Month 12 in Cardiovascular Risk (Framingham Score; 10-year Cardiovascular Risk) | Baseline 2/Month 3 (n=165,171,161) | 8.8 Percent risk | Standard Deviation 5.9 |
| CNI Low Regimen | Change From BL2 (Month 3) to Month 12 in Cardiovascular Risk (Framingham Score; 10-year Cardiovascular Risk) | Change from Baseline 2 to Month 12 (n=158,166,156) | -0.7 Percent risk | Standard Deviation 5.4 |
| CNI Low Regimen | Change From BL2 (Month 3) to Month 12 in Cardiovascular Risk (Framingham Score; 10-year Cardiovascular Risk) | Baseline 2/Month 3 (n=165,171,161) | 9.3 Percent risk | Standard Deviation 7.2 |
| CNI Low Regimen | Change From BL2 (Month 3) to Month 12 in Cardiovascular Risk (Framingham Score; 10-year Cardiovascular Risk) | Month 12 (n=158,166,156) | 8.7 Percent risk | Standard Deviation 6.8 |
| CNI Low Regimen | Change From BL2 (Month 3) to Month 12 in Cardiovascular Risk (Framingham Score; 10-year Cardiovascular Risk) | Baseline 1/Visit 1 (n=165,171,161) | 9.5 Percent risk | Standard Deviation 6.9 |
Secondary
Efficacy Event Data After Month 12 to Month 60
Efficacy events were: Biopsy-proven acute rejection (BPAR), graft loss, death, and treatment failure (defined as composite endpoint of BPAR, graft loss, death, loss to follow-up, discontinuation due to lack of efficacy or due to toxicity).
Time frame: Events starting after Month 12
Population: The Intention-to-treat (ITT) Population consisted of all patients who were randomized at BL2 (Month 3), and who received at least one dose of randomized treatment. Patients were analyzed according to their assigned treatment. The ITT population might have included patients without any data after randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Standard Regimen | Efficacy Event Data After Month 12 to Month 60 | Death | 7 Participants |
| Standard Regimen | Efficacy Event Data After Month 12 to Month 60 | BPAR | 13 Participants |
| Standard Regimen | Efficacy Event Data After Month 12 to Month 60 | Lost to follow-up | 17 Participants |
| Standard Regimen | Efficacy Event Data After Month 12 to Month 60 | Graft loss | 7 Participants |
| Standard Regimen | Efficacy Event Data After Month 12 to Month 60 | Therapy failure (composite endpoint) | 38 Participants |
| Standard Regimen | Efficacy Event Data After Month 12 to Month 60 | Discontinuation due to adverse event | 10 Participants |
| CNI Free Regimen | Efficacy Event Data After Month 12 to Month 60 | BPAR | 13 Participants |
| CNI Free Regimen | Efficacy Event Data After Month 12 to Month 60 | Graft loss | 7 Participants |
| CNI Free Regimen | Efficacy Event Data After Month 12 to Month 60 | Death | 4 Participants |
| CNI Free Regimen | Efficacy Event Data After Month 12 to Month 60 | Lost to follow-up | 15 Participants |
| CNI Free Regimen | Efficacy Event Data After Month 12 to Month 60 | Discontinuation due to adverse event | 8 Participants |
| CNI Free Regimen | Efficacy Event Data After Month 12 to Month 60 | Therapy failure (composite endpoint) | 35 Participants |
| CNI Low Regimen | Efficacy Event Data After Month 12 to Month 60 | Graft loss | 3 Participants |
| CNI Low Regimen | Efficacy Event Data After Month 12 to Month 60 | Therapy failure (composite endpoint) | 36 Participants |
| CNI Low Regimen | Efficacy Event Data After Month 12 to Month 60 | Discontinuation due to adverse event | 4 Participants |
| CNI Low Regimen | Efficacy Event Data After Month 12 to Month 60 | Death | 9 Participants |
| CNI Low Regimen | Efficacy Event Data After Month 12 to Month 60 | BPAR | 12 Participants |
| CNI Low Regimen | Efficacy Event Data After Month 12 to Month 60 | Lost to follow-up | 13 Participants |
Secondary
Efficacy Event Data Baseline 2 (Month 3) to Month 12
Efficacy events were: Biopsy-proven acute rejection (BPAR), graft loss, death, and treatment failure (defined as composite endpoint of BPAR, graft loss, death, loss to follow-up, discontinuation due to lack of efficacy or due to toxicity).
Time frame: From Baseline 2 (Month 3) to Month 12
Population: The Intention-to-treat (ITT) Population consisted of all patients who were randomized at BL2 (Month 3), and who received at least one dose of randomized treatment. Patients were analyzed according to their assigned treatment. The ITT population might have included patients without any data after randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Standard Regimen | Efficacy Event Data Baseline 2 (Month 3) to Month 12 | Graft loss | 1 Participants |
| Standard Regimen | Efficacy Event Data Baseline 2 (Month 3) to Month 12 | Discontinuation due to lack of efficacy | 2 Participants |
| Standard Regimen | Efficacy Event Data Baseline 2 (Month 3) to Month 12 | Lost to follow-up | 0 Participants |
| Standard Regimen | Efficacy Event Data Baseline 2 (Month 3) to Month 12 | BPAR | 13 Participants |
| Standard Regimen | Efficacy Event Data Baseline 2 (Month 3) to Month 12 | Therapy failure composite | 34 Participants |
| Standard Regimen | Efficacy Event Data Baseline 2 (Month 3) to Month 12 | Discontinuation due to adverse event | 25 Participants |
| Standard Regimen | Efficacy Event Data Baseline 2 (Month 3) to Month 12 | Death | 3 Participants |
| CNI Free Regimen | Efficacy Event Data Baseline 2 (Month 3) to Month 12 | Lost to follow-up | 0 Participants |
| CNI Free Regimen | Efficacy Event Data Baseline 2 (Month 3) to Month 12 | BPAR | 20 Participants |
| CNI Free Regimen | Efficacy Event Data Baseline 2 (Month 3) to Month 12 | Graft loss | 2 Participants |
| CNI Free Regimen | Efficacy Event Data Baseline 2 (Month 3) to Month 12 | Death | 2 Participants |
| CNI Free Regimen | Efficacy Event Data Baseline 2 (Month 3) to Month 12 | Discontinuation due to lack of efficacy | 3 Participants |
| CNI Free Regimen | Efficacy Event Data Baseline 2 (Month 3) to Month 12 | Discontinuation due to adverse event | 44 Participants |
| CNI Free Regimen | Efficacy Event Data Baseline 2 (Month 3) to Month 12 | Therapy failure composite | 58 Participants |
| CNI Low Regimen | Efficacy Event Data Baseline 2 (Month 3) to Month 12 | Discontinuation due to lack of efficacy | 1 Participants |
| CNI Low Regimen | Efficacy Event Data Baseline 2 (Month 3) to Month 12 | Graft loss | 1 Participants |
| CNI Low Regimen | Efficacy Event Data Baseline 2 (Month 3) to Month 12 | Therapy failure composite | 35 Participants |
| CNI Low Regimen | Efficacy Event Data Baseline 2 (Month 3) to Month 12 | Discontinuation due to adverse event | 27 Participants |
| CNI Low Regimen | Efficacy Event Data Baseline 2 (Month 3) to Month 12 | Lost to follow-up | 0 Participants |
| CNI Low Regimen | Efficacy Event Data Baseline 2 (Month 3) to Month 12 | Death | 2 Participants |
| CNI Low Regimen | Efficacy Event Data Baseline 2 (Month 3) to Month 12 | BPAR | 13 Participants |
Secondary
Efficacy Event Data From Baseline 2 (Month 3) to Month 6
Efficacy events were: Biopsy-proven acute rejection (BPAR), graft loss, death, and treatment failure (defined as composite endpoint of BPAR, graft loss, death, loss to follow-up, discontinuation due to lack of efficacy or due to toxicity).
Time frame: From Baseline 2 (Month 3) to Month 6
Population: The Intention-to-treat (ITT) Population consisted of all patients who were randomized at BL2 (Month 3), and who received at least one dose of randomized treatment. Patients were analyzed according to their assigned treatment. The ITT population might have included patients without any data after randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Standard Regimen | Efficacy Event Data From Baseline 2 (Month 3) to Month 6 | Graft loss | 0 Participants |
| Standard Regimen | Efficacy Event Data From Baseline 2 (Month 3) to Month 6 | Discontinuation due to lack of efficacy | 1 Participants |
| Standard Regimen | Efficacy Event Data From Baseline 2 (Month 3) to Month 6 | Lost to follow-up | 0 Participants |
| Standard Regimen | Efficacy Event Data From Baseline 2 (Month 3) to Month 6 | BPAR | 6 Participants |
| Standard Regimen | Efficacy Event Data From Baseline 2 (Month 3) to Month 6 | Therapy failure composite | 14 Participants |
| Standard Regimen | Efficacy Event Data From Baseline 2 (Month 3) to Month 6 | Discontinuation due to adverse event | 8 Participants |
| Standard Regimen | Efficacy Event Data From Baseline 2 (Month 3) to Month 6 | Death | 1 Participants |
| CNI Free Regimen | Efficacy Event Data From Baseline 2 (Month 3) to Month 6 | Lost to follow-up | 0 Participants |
| CNI Free Regimen | Efficacy Event Data From Baseline 2 (Month 3) to Month 6 | BPAR | 15 Participants |
| CNI Free Regimen | Efficacy Event Data From Baseline 2 (Month 3) to Month 6 | Graft loss | 1 Participants |
| CNI Free Regimen | Efficacy Event Data From Baseline 2 (Month 3) to Month 6 | Death | 1 Participants |
| CNI Free Regimen | Efficacy Event Data From Baseline 2 (Month 3) to Month 6 | Discontinuation due to lack of efficacy | 2 Participants |
| CNI Free Regimen | Efficacy Event Data From Baseline 2 (Month 3) to Month 6 | Discontinuation due to adverse event | 26 Participants |
| CNI Free Regimen | Efficacy Event Data From Baseline 2 (Month 3) to Month 6 | Therapy failure composite | 37 Participants |
| CNI Low Regimen | Efficacy Event Data From Baseline 2 (Month 3) to Month 6 | Discontinuation due to lack of efficacy | 1 Participants |
| CNI Low Regimen | Efficacy Event Data From Baseline 2 (Month 3) to Month 6 | Graft loss | 1 Participants |
| CNI Low Regimen | Efficacy Event Data From Baseline 2 (Month 3) to Month 6 | Therapy failure composite | 19 Participants |
| CNI Low Regimen | Efficacy Event Data From Baseline 2 (Month 3) to Month 6 | Discontinuation due to adverse event | 13 Participants |
| CNI Low Regimen | Efficacy Event Data From Baseline 2 (Month 3) to Month 6 | Lost to follow-up | 0 Participants |
| CNI Low Regimen | Efficacy Event Data From Baseline 2 (Month 3) to Month 6 | Death | 0 Participants |
| CNI Low Regimen | Efficacy Event Data From Baseline 2 (Month 3) to Month 6 | BPAR | 10 Participants |
Secondary
GFR at Month 12 Utilizing Cockcroft-Gault Formula
Cockcroft-Gault formula: For men: GFR= ((140-age) × body weight in kg)∕(72 x serum creatinine in mg∕dl)For women: GFR= (0.85×(140-age) × body weight in kg)∕(72 x serum creatinine in mg/dl), ), last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model
Time frame: From randomization at BL2 (Month 3) to Month 12 post-transplant
Population: Participants analyzed differs due to different input values requested by the different formulas (Nankivell, MDRD and Cockcroft-Gault). ITT Population consisted of all patients who were randomized at Month 3 who received at least one dose of randomized treatment. The ITT population might have included patients without any data after randomization.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Standard Regimen | GFR at Month 12 Utilizing Cockcroft-Gault Formula | 60.18 ml/min/1.73m² |
| CNI Free Regimen | GFR at Month 12 Utilizing Cockcroft-Gault Formula | 64.87 ml/min/1.73m² |
| CNI Low Regimen | GFR at Month 12 Utilizing Cockcroft-Gault Formula | 61.16 ml/min/1.73m² |
Secondary
GFR at Month 12 Utilizing Modification of Diet in Renal Disease (MDRD) Method
Change in GFR (Modification of Diet in Renal Disease calculated using the -MDRD formulat: For men: GFR = 170 × (serum creatinine -0,999)×(age-0,176) x (urea nitrogen -0,17) × (albumin0,318) For women: GFR = 170 × (serum creatinine -0,999) × (age-0,176) × (urea nitrogen -0,17) x (albumin0,318) × 0.762 with urea nitrogen = urea / 2.144. ), last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model, with treatment, center, donor type (deceased vs. living) as factors and BL2-value at V4/M3/BL2 as covariate.
Time frame: From randomization at BL2 (Month 3) to Month 12 post-transplant
Population: Participants analyzed differs due to different input values requested by the different formulas (Nankivell, MDRD and Cockcroft-Gault). ITT Population consisted of all patients who were randomized at Month 3 who received at least one dose of randomized treatment. The ITT population might have included patients without any data after randomization.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Standard Regimen | GFR at Month 12 Utilizing Modification of Diet in Renal Disease (MDRD) Method | 50.23 ml/min/1.73m² |
| CNI Free Regimen | GFR at Month 12 Utilizing Modification of Diet in Renal Disease (MDRD) Method | 56.36 ml/min/1.73m² |
| CNI Low Regimen | GFR at Month 12 Utilizing Modification of Diet in Renal Disease (MDRD) Method | 50.24 ml/min/1.73m² |
Secondary
GFR at Month 60 Utilizing Cockcroft-Gault Formula
Cockcroft-Gault formula: For men: GFR= ((140-age) × body weight in kg)∕(72 x serum creatinine in mg∕dl) For women: GFR= (0.85×(140-age) × body weight in kg)∕(72 x serum creatinine in mg/dl), ), last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model
Time frame: From randomization at BL2 (Month 3) to Month 60 post-transplant
Population: Participants analyzed differs due to different input values requested by the different formulas (Nankivell, MDRD and Cockcroft-Gault). ITT Population consisted of all patients who were randomized at Month 3 who received at least one dose of randomized treatment. The ITT population might have included patients without any data after randomization
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Standard Regimen | GFR at Month 60 Utilizing Cockcroft-Gault Formula | 55.92 ml/min/1.73m² |
| CNI Free Regimen | GFR at Month 60 Utilizing Cockcroft-Gault Formula | 61.6 ml/min/1.73m² |
| CNI Low Regimen | GFR at Month 60 Utilizing Cockcroft-Gault Formula | 52.91 ml/min/1.73m² |
Secondary
GFR at Month 60 Utilizing Modification of Diet in Renal Disease (MDRD) Method
Change in GFR (Modification of Diet in Renal Disease calculated using the -MDRD formulat: For men: GFR = 170 × (serum creatinine -0,999)×(age-0,176) x (urea nitrogen -0,17) × (albumin0,318) For women: GFR = 170 × (serum creatinine -0,999) × (age-0,176) × (urea nitrogen -0,17) x (albumin0,318) × 0.762 with urea nitrogen = urea / 2.144. ), last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model, with treatment, center, donor type (deceased vs. living) as factors and BL2-value at V4/M3/BL2 as covariate.
Time frame: From randomization at BL2 (Month 3) to Month 60 post-transplant
Population: Participants analyzed differs due to different input values requested by the different formulas (Nankivell, MDRD and Cockcroft-Gault). ITT Population consisted of all patients who were randomized at Month 3 who received at least one dose of randomized treatment. The ITT population might have included patients without any data after randomization
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Standard Regimen | GFR at Month 60 Utilizing Modification of Diet in Renal Disease (MDRD) Method | 47.56 ml/min/1.73m² |
| CNI Free Regimen | GFR at Month 60 Utilizing Modification of Diet in Renal Disease (MDRD) Method | 53.41 ml/min/1.73m² |
| CNI Low Regimen | GFR at Month 60 Utilizing Modification of Diet in Renal Disease (MDRD) Method | 44.79 ml/min/1.73m² |
Secondary
GFR Calculated Via Nankivell Formula at Month 60
Change in GFR using the Nankivell formula (GFR = 6.7 / Scr + BW / 4 - Surea / 2-100 / (height)² + C where where Scr is the serum creatinine concentration expressed in mmol/L, BW the body weight in kilograms, Surea the serum urea in mmol/L, height in m, and the constant C is 35 for male and 25 for female patients. The calculated GFR is expressed in mL/min per 1.73m², last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model, with treatment, center, donor type (deceased vs. living) as factors and BL2-value at V4/M3/BL2 as covariate.
Time frame: From randomization at BL2 (Month 3) to Month 60
Population: Participants analyzed differs due to different input values requested by the different formulas (Nankivell, MDRD and Cockcroft-Gault). ITT Population consisted of all patients who were randomized at Month 3 who received at least one dose of randomized treatment. The ITT population might have included patients without any data after randomization
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Standard Regimen | GFR Calculated Via Nankivell Formula at Month 60 | 60.24 ml/min/1.73m² |
| CNI Free Regimen | GFR Calculated Via Nankivell Formula at Month 60 | 66.98 ml/min/1.73m² |
| CNI Low Regimen | GFR Calculated Via Nankivell Formula at Month 60 | 58.74 ml/min/1.73m² |
Secondary
GFR Via Nankivell Formula at Month 12 - All Regimens
Change in GFR using the Nankivell formula (GFR = 6.7 / Scr + BW / 4 - Surea / 2-100 / (height)² + C where where Scr is the serum creatinine concentration expressed in mmol/L, BW the body weight in kilograms, Surea the serum urea in mmol/L, height in m, and the constant C is 35 for male and 25 for female patients. The calculated GFR is expressed in mL/min per 1.73m², last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model, with treatment, center, donor type (deceased vs. living) as factors and BL2-value at V4/M3/BL2 as covariate.
Time frame: From randomization at BL2 (Month 3) to Month 12 post-transplant
Population: Participants analyzed differs due to different input values requested by the different formulas (Nankivell, MDRD and Cockcroft-Gault). ITT Population consisted of all patients who were randomized at Month 3 who received at least one dose of randomized treatment. The ITT population might have included patients without any data after randomization.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Standard Regimen | GFR Via Nankivell Formula at Month 12 - All Regimens | 63.03 ml/min/1.73m² |
| CNI Free Regimen | GFR Via Nankivell Formula at Month 12 - All Regimens | 68.59 ml/min/1.73m² |
| CNI Low Regimen | GFR Via Nankivell Formula at Month 12 - All Regimens | 63.08 ml/min/1.73m² |
Secondary
Mean Change in Serum Creatinine From Month 3 to Month 12
Change in venous blood serum creatinine. Last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model
Time frame: From randomization at BL2 (Month 3) to Month 12 post-transplant
Population: Participants analyzed required at least one post randomization value. ITT Population consisted of all patients who were randomized at Month 3 who received at least one dose of randomized treatment. The ITT population might have included patients without any data after randomization
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Standard Regimen | Mean Change in Serum Creatinine From Month 3 to Month 12 | 1.66 mg/dl |
| CNI Free Regimen | Mean Change in Serum Creatinine From Month 3 to Month 12 | 1.58 mg/dl |
| CNI Low Regimen | Mean Change in Serum Creatinine From Month 3 to Month 12 | 1.76 mg/dl |
Secondary
Mean Change in Serum Creatinine From Month 3 to Month 60
Change in venous blood serum creatinine. Last observation carried forward (LOCF) was used for imputation of missing values, ANCOVA model
Time frame: From randomization at BL2 (Month 3) to Month 60 post-transplant
Population: Participants analyzed were previously enrolled in the core study and had at least one serum creatinine value in the extension period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Standard Regimen | Mean Change in Serum Creatinine From Month 3 to Month 60 | 1.94 mg/dl |
| CNI Free Regimen | Mean Change in Serum Creatinine From Month 3 to Month 60 | 1.69 mg/dl |
| CNI Low Regimen | Mean Change in Serum Creatinine From Month 3 to Month 60 | 2.01 mg/dl |