Kidney Diseases
Conditions
Keywords
Dose optimization, immune suppressive regimen, enteric-coated mycophenolate sodium, EC-MPS, renal transplantation, kidney, transplant, maintenance patients, Renal transplantation in maintenance
Brief summary
This study introduces a new optimization immunosuppressive regimen associating tacrolimus at a reduced dose and enteric-coated mycophenolate sodium at an increased dose in order to slow down renal function worsening and to prevent the progression of chronic allograft nephropathy, while maintaining the same efficacy, in maintenance renal transplant recipients.
Interventions
DRUGEnteric-coated mycophenolate sodium (EC-MPS)
DRUGTacrolimus
DRUGCorticosteroids
At a dose of at least 5 mg/day.
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Primary or secondary kidney transplant * Treatment with mycophenolic acid (MMF 1 g/d or EC-MPS 720 mg/d) and tacrolimus (trough concentration \[C0\] ≥ 5.5 ng/mL) * Creatinine clearance ≥ 30 mL/min and \< 60 mL/min and stable renal function
Exclusion criteria
* Multi-organ recipients or previous transplant with any other organ different from kidney * Biopsy proven acute rejection or treated acute rejection within the last 3 months. * Prescription of mycophenolate mofetil 1 g/d or mycophenolate sodium 720 mg/d due to adverse event occurrence when higher doses were administered Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Renal Function Assessed by Change in Estimated Glomerular Filtration Rate(eGFR) | Baseline and Month 6 | Change in estimated glomerular filtration rate from baseline to Month 6 calculated by using abbreviated Modification of Diet in Renal Disease (MDRD) formula. Modification of Diet in Renal Disease (MDRD) formula is: GFR \[mL/min/1.73m\^2\] = 186.3\*(C\^-1.154)\*(A\^-0.203)\*G\*R where -C is the serum concentration of creatinine \[mg/dL\], -A is patient age at sample collection date \[years\], -G=0.742 when gender is female, otherwise G=1, -R=1.21 when race is black, otherwise R=1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Renal Function at 3 Months Assessed by Change in Estimated Glomerular Filtration Rate (eGFR) | Baseline and 3 months | Change in estimated glomerular filtration rate from baseline to Month 3 calculated by using abbreviated MDRD formula. Modification of Diet in Renal Disease (MDRD) formula is: GFR \[mL/min/1.73m\^2\] = 186.3\*(C\^-1.154)\*(A\^-0.203)\*G\*R where -C is the serum concentration of creatinine \[mg/dL\], -A is patient age at sample collection date \[years\], -G=0.742 when gender is female, otherwise G=1, -R=1.21 when race is black, otherwise R=1. |
| Number of Participants With Treatment Failure Parameters (Biopsy-Proven Acute Rejection (BPAR), Graft Loss, Death, or Loss to Follow-up) at 6 Months | 6 months | A biopsy-proven acute rejection (BPAR) is defined as a biopsy graded IA, IB, IIA, IIB, or III based on the Banff 1997 classification.The allograft was presumed lost on the day the patient started dialysis and was not able to subsequently be removed from dialysis. If the patient went through a graft nephrectomy, then the day of nephrectomy was the day of graft loss. |
| Number of Participants With Graft and Patient Survivals at 6 Months | 6 months | Graft survival was defined as the number of patients with no graft loss. The allograft was presumed lost on the day the patient started dialysis and was not able to subsequently be removed from dialysis. If the patient went through a graft nephrectomy, then the day of nephrectomy was the day of graft loss. Patient survival was defined as the number of patients alive with or without a functioning graft. |
Countries
Switzerland
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Standard Dose EC-MPS Patients received 720 mg/day (360 mg twice a day (bid) orally) Enteric-coated mycophenolate sodium (EC-MPS) and tacrolimus (twice a day orally) dose adjusted to maintain a trough blood level (C0) between 5.5 and 10 ng/mL. The randomization was stratified on 1 factor: treatment with or without steroids. Prednisone (or oral equivalent) was administrated to patients as before entering the study and as per center's standard practice, but at a dose of at least 5 mg/day. | 47 |
| High EC-MPS Patients received 1440 mg/day (720 mg twice a day orally) Enteric-coated mycophenolate sodium (EC-MPS) and tacrolimus (twice a day orally) dose tapered to reach a trough blood level target of between 2 and 4.5 ng/mL within 15 days after randomization. The randomization was stratified on 1 factor: treatment with or without steroids. Prednisone (or oral equivalent) was administrated to patients as before entering the study and as per center's standard practice, but at a dose of at least 5 mg/day. | 45 |
| Total | 92 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Other reasons | 3 | 1 |
Baseline characteristics
| Characteristic | Standard Dose EC-MPS | High EC-MPS | Total |
|---|---|---|---|
| Age Continuous | 54.5 Years STANDARD_DEVIATION 10.4 | 50.7 Years STANDARD_DEVIATION 12.2 | 52.7 Years STANDARD_DEVIATION 11 |
| Age, Customized < 45 | 11 Participants | 13 Participants | 24 Participants |
| Age, Customized 45-60 | 18 Participants | 20 Participants | 38 Participants |
| Age, Customized >= 60 | 18 Participants | 12 Participants | 30 Participants |
| Sex: Female, Male Female | 16 Participants | 15 Participants | 31 Participants |
| Sex: Female, Male Male | 31 Participants | 30 Participants | 61 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 47 | 10 / 45 |
| serious Total, serious adverse events | 8 / 47 | 7 / 45 |
Outcome results
Primary
Renal Function Assessed by Change in Estimated Glomerular Filtration Rate(eGFR)
Change in estimated glomerular filtration rate from baseline to Month 6 calculated by using abbreviated Modification of Diet in Renal Disease (MDRD) formula. Modification of Diet in Renal Disease (MDRD) formula is: GFR \[mL/min/1.73m\^2\] = 186.3\*(C\^-1.154)\*(A\^-0.203)\*G\*R where -C is the serum concentration of creatinine \[mg/dL\], -A is patient age at sample collection date \[years\], -G=0.742 when gender is female, otherwise G=1, -R=1.21 when race is black, otherwise R=1.
Time frame: Baseline and Month 6
Population: Intent-to-treat (ITT) population was defined as all patients who were randomized and treated with study medication and had at least one post-treatment efficacy assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Standard Dose EC-MPS | Renal Function Assessed by Change in Estimated Glomerular Filtration Rate(eGFR) | Baseline (n= 47, 45) | 45.3 mL/min/1.73m^2 | Standard Deviation 9.5 |
| Standard Dose EC-MPS | Renal Function Assessed by Change in Estimated Glomerular Filtration Rate(eGFR) | Month 6 (n= 45, 43) | 44.7 mL/min/1.73m^2 | Standard Deviation 11.5 |
| Standard Dose EC-MPS | Renal Function Assessed by Change in Estimated Glomerular Filtration Rate(eGFR) | Change from Baseline - Month 6 (n= 45, 43) | -0.4 mL/min/1.73m^2 | Standard Deviation 6.9 |
| High EC-MPS | Renal Function Assessed by Change in Estimated Glomerular Filtration Rate(eGFR) | Baseline (n= 47, 45) | 56.4 mL/min/1.73m^2 | Standard Deviation 11.2 |
| High EC-MPS | Renal Function Assessed by Change in Estimated Glomerular Filtration Rate(eGFR) | Month 6 (n= 45, 43) | 49.1 mL/min/1.73m^2 | Standard Deviation 11.11 |
| High EC-MPS | Renal Function Assessed by Change in Estimated Glomerular Filtration Rate(eGFR) | Change from Baseline - Month 6 (n= 45, 43) | 2.4 mL/min/1.73m^2 | Standard Deviation 6.1 |
Secondary
Number of Participants With Graft and Patient Survivals at 6 Months
Graft survival was defined as the number of patients with no graft loss. The allograft was presumed lost on the day the patient started dialysis and was not able to subsequently be removed from dialysis. If the patient went through a graft nephrectomy, then the day of nephrectomy was the day of graft loss. Patient survival was defined as the number of patients alive with or without a functioning graft.
Time frame: 6 months
Population: Intent-to-treat (ITT) population was defined as all patients who were randomized and treated with study medication and had at least one post-treatment efficacy assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Standard Dose EC-MPS | Number of Participants With Graft and Patient Survivals at 6 Months | Graft survival | 47 Participants |
| Standard Dose EC-MPS | Number of Participants With Graft and Patient Survivals at 6 Months | Patient survival | 47 Participants |
| High EC-MPS | Number of Participants With Graft and Patient Survivals at 6 Months | Graft survival | 45 Participants |
| High EC-MPS | Number of Participants With Graft and Patient Survivals at 6 Months | Patient survival | 45 Participants |
Secondary
Number of Participants With Treatment Failure Parameters (Biopsy-Proven Acute Rejection (BPAR), Graft Loss, Death, or Loss to Follow-up) at 6 Months
A biopsy-proven acute rejection (BPAR) is defined as a biopsy graded IA, IB, IIA, IIB, or III based on the Banff 1997 classification.The allograft was presumed lost on the day the patient started dialysis and was not able to subsequently be removed from dialysis. If the patient went through a graft nephrectomy, then the day of nephrectomy was the day of graft loss.
Time frame: 6 months
Population: Intent-to-treat (ITT) population was defined as all patients who were randomized and treated with study medication and had at least one post-treatment efficacy assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Standard Dose EC-MPS | Number of Participants With Treatment Failure Parameters (Biopsy-Proven Acute Rejection (BPAR), Graft Loss, Death, or Loss to Follow-up) at 6 Months | Biopsy proven acute rejection | 0 Participants |
| Standard Dose EC-MPS | Number of Participants With Treatment Failure Parameters (Biopsy-Proven Acute Rejection (BPAR), Graft Loss, Death, or Loss to Follow-up) at 6 Months | Treated acute rejection | 0 Participants |
| Standard Dose EC-MPS | Number of Participants With Treatment Failure Parameters (Biopsy-Proven Acute Rejection (BPAR), Graft Loss, Death, or Loss to Follow-up) at 6 Months | Graft loss | 0 Participants |
| Standard Dose EC-MPS | Number of Participants With Treatment Failure Parameters (Biopsy-Proven Acute Rejection (BPAR), Graft Loss, Death, or Loss to Follow-up) at 6 Months | Death | 0 Participants |
| High EC-MPS | Number of Participants With Treatment Failure Parameters (Biopsy-Proven Acute Rejection (BPAR), Graft Loss, Death, or Loss to Follow-up) at 6 Months | Death | 0 Participants |
| High EC-MPS | Number of Participants With Treatment Failure Parameters (Biopsy-Proven Acute Rejection (BPAR), Graft Loss, Death, or Loss to Follow-up) at 6 Months | Biopsy proven acute rejection | 0 Participants |
| High EC-MPS | Number of Participants With Treatment Failure Parameters (Biopsy-Proven Acute Rejection (BPAR), Graft Loss, Death, or Loss to Follow-up) at 6 Months | Graft loss | 0 Participants |
| High EC-MPS | Number of Participants With Treatment Failure Parameters (Biopsy-Proven Acute Rejection (BPAR), Graft Loss, Death, or Loss to Follow-up) at 6 Months | Treated acute rejection | 0 Participants |
Secondary
Renal Function at 3 Months Assessed by Change in Estimated Glomerular Filtration Rate (eGFR)
Change in estimated glomerular filtration rate from baseline to Month 3 calculated by using abbreviated MDRD formula. Modification of Diet in Renal Disease (MDRD) formula is: GFR \[mL/min/1.73m\^2\] = 186.3\*(C\^-1.154)\*(A\^-0.203)\*G\*R where -C is the serum concentration of creatinine \[mg/dL\], -A is patient age at sample collection date \[years\], -G=0.742 when gender is female, otherwise G=1, -R=1.21 when race is black, otherwise R=1.
Time frame: Baseline and 3 months
Population: Intent-to-treat (ITT) population was defined as all patients who were randomized and treated with study medication and had at least one post-treatment efficacy assessment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Standard Dose EC-MPS | Renal Function at 3 Months Assessed by Change in Estimated Glomerular Filtration Rate (eGFR) | Baseline (n= 47, 45) | 45.3 mL/min/1.73m^2 | Standard Deviation 9.5 |
| Standard Dose EC-MPS | Renal Function at 3 Months Assessed by Change in Estimated Glomerular Filtration Rate (eGFR) | Month 3 (n= 44, 43) | 44.6 mL/min/1.73m^2 | Standard Deviation 10.9 |
| Standard Dose EC-MPS | Renal Function at 3 Months Assessed by Change in Estimated Glomerular Filtration Rate (eGFR) | Change from Baseline to Month 3 (n= 44, 43) | -0.4 mL/min/1.73m^2 | Standard Deviation 4.6 |
| High EC-MPS | Renal Function at 3 Months Assessed by Change in Estimated Glomerular Filtration Rate (eGFR) | Baseline (n= 47, 45) | 46.4 mL/min/1.73m^2 | Standard Deviation 11.2 |
| High EC-MPS | Renal Function at 3 Months Assessed by Change in Estimated Glomerular Filtration Rate (eGFR) | Month 3 (n= 44, 43) | 48.6 mL/min/1.73m^2 | Standard Deviation 10.8 |
| High EC-MPS | Renal Function at 3 Months Assessed by Change in Estimated Glomerular Filtration Rate (eGFR) | Change from Baseline to Month 3 (n= 44, 43) | 2.1 mL/min/1.73m^2 | Standard Deviation 4.9 |