Renal Transplantation
Conditions
Keywords
Renal transplantation, mycophenolate
Brief summary
This study will assess the association of an initially intensified dosing regimen of enteric-coated mycophenolate sodium (EC-MPS) during the first 6 weeks post renal transplantation with acute rejections relative to the rapid achievement of an MPA (mycophenolic acid) exposure of ≥ 40 mg\*h/L compared to a standard dosing regimen of EC-MPS. Additionally, this study will assess safety and tolerability of the intensified dosing regimen of EC-MPS. This study will be conducted in 2 stages (Stage I and Stage II).
Interventions
DRUGEnteric-coated mycophenolate sodium (EC-MPS)
Tablets for oral administration
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
Inclusion criteria
1. Recipients of de novo cadaveric, living unrelated or living related kidney transplants 2. Females capable of becoming pregnant must have a negative serum pregnancy test within 7 days prior to or at baseline, 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. 3. Patients who are willing and able to participate in the study and from whom written informed consent has been obtained.
Exclusion criteria
1. More than one previous renal transplantation 2. Graft loss due to immunological reasons in the first year after transplantation (in case of secondary transplantation) 3. Multi-organ recipients (e.g., kidney and pancreas) or previous transplant with any other organ, different from kidney 4. Patients receiving a kidney from a non-heart beating donor 5. Patients who are recipients of A-B-O incompatible transplants Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Occurrence of a Mycophenolic Acid (MPA) Plasma Concentration of ≥ 40 mg*h/L | Assessed on day 3, 10, 21, 42, 56 and 84 | Non-compartmental MPA pharmacokinetic parameters were derived from individual plasma concentration-time profiles using WinNonLin 5.2 software. The areas under the curve were calculated by means of the linear trapezoidal rule. |
| Time to First Occurrence of Any Treatment Failure During the First 6 Months Post-treatment or at Month 6 Post-treatment | 6 months | Median time to first occurrence of treatment failure was not reached in this study. |
| Number of Participants With Any Treatment Failure | 6 months | Treatment failures were defined as a composite endpoint of biopsy proven acute rejection (BPAR), graft loss, and death, loss to follow up and discontinuations from study drug treatment due to lack of efficacy or toxicity (at least one condition must be present) during the first 6 months or until final assessment. Any participants who were suspected of having acute rejection episodes had biopsies performed to prove whether a rejection had occurred. Graft loss was considered as the day the patient started dialysis and was not able to subsequently be removed or the day of graft nephrectomy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Renal Function as Measured by Serum Creatinine | 6 months | — |
| Number of Participants With Single Treatment Failures | 6 months | Rates for all individual components of the primary endpoint 'treatment failure' until day 180: * Acute rejection diagnosed by biopsy (BPAR) * graft loss * death * loss to follow up * discontinuation from study drug due to lack of efficacy or toxicity (adverse events, every adverse event had to be interpreted as toxicity) * conversion to another dosing regimen (conversion to tacrolimus, prograf, etc.) |
| Renal Function as Measured by Glomerular Filtration Rate (GFR) | 6 months | The Glomerular Filtration Rate (GFR) was calculated using the following formulas: * Cockcroft-Gault formula: calculation using the participant's age, gender, weight, and serum creatinine levels. * MDRD formula: calculation using the participant's age, gender, serum creatinine, urea nitrogen, and albumin levels. |
| Rates of Events for Treated Acute Rejection, Death, Graft Loss, or Loss to Follow up on Day 28, Day 84, and Day 180 | 6 months | Due to a small number of events, median time to \<event\> was not reached. |
| Time to Event for the Composite Endpoint as Well as All Individual Components of That Endpoint Treatment Failure Including Clinical Rejections | 6 months | Due to a small number of events, median time to \<event\> was not reached. |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Intensified Mycophenolate Sodium Enteric-coated mycophenolate sodium was given according to the following dosing regimen: Day 1-14: 2880 mg/day (2 x 1440 mg), then day 15-42: 2160 mg/day (2 x 1080 mg), then day 43-End of study (month 6): 1440 mg/day (2 x 720 mg) | 63 |
| Standard Mycophenolate Sodium Enteric-coated mycophenolate sodium was given according to the following dosing regimen: Day 1 - End of Study(month 6): 1440 mg/day (2 x 720 mg) | 65 |
| Total | 128 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 14 | 11 |
| Overall Study | Graft loss | 1 | 2 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Protocol Violation | 2 | 1 |
| Overall Study | Unsatisfactory therapeutic effect | 4 | 5 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Intensified Mycophenolate Sodium | Standard Mycophenolate Sodium | Total |
|---|---|---|---|
| Age Continuous | 52.4 years STANDARD_DEVIATION 12.5 | 50.4 years STANDARD_DEVIATION 14.6 | 51.4 years STANDARD_DEVIATION 13.6 |
| Sex: Female, Male Female | 29 Participants | 30 Participants | 59 Participants |
| Sex: Female, Male Male | 34 Participants | 35 Participants | 69 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 62 / 63 | 63 / 65 |
| serious Total, serious adverse events | 44 / 63 | 40 / 65 |
Outcome results
Primary
Number of Participants With Any Treatment Failure
Treatment failures were defined as a composite endpoint of biopsy proven acute rejection (BPAR), graft loss, and death, loss to follow up and discontinuations from study drug treatment due to lack of efficacy or toxicity (at least one condition must be present) during the first 6 months or until final assessment. Any participants who were suspected of having acute rejection episodes had biopsies performed to prove whether a rejection had occurred. Graft loss was considered as the day the patient started dialysis and was not able to subsequently be removed or the day of graft nephrectomy.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intensified Mycophenolate Sodium | Number of Participants With Any Treatment Failure | 19 Participants |
| Standard Mycophenolate Sodium | Number of Participants With Any Treatment Failure | 24 Participants |
Primary
Time to First Occurrence of a Mycophenolic Acid (MPA) Plasma Concentration of ≥ 40 mg*h/L
Non-compartmental MPA pharmacokinetic parameters were derived from individual plasma concentration-time profiles using WinNonLin 5.2 software. The areas under the curve were calculated by means of the linear trapezoidal rule.
Time frame: Assessed on day 3, 10, 21, 42, 56 and 84
Population: Pharmacokinetic profiles were performed only in patients involved in Phase I of the study. The pharmacokinetic population consisted of 42 participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Intensified Mycophenolate Sodium | Time to First Occurrence of a Mycophenolic Acid (MPA) Plasma Concentration of ≥ 40 mg*h/L | 7.00 Days |
| Standard Mycophenolate Sodium | Time to First Occurrence of a Mycophenolic Acid (MPA) Plasma Concentration of ≥ 40 mg*h/L | 43.00 Days |
Primary
Time to First Occurrence of Any Treatment Failure During the First 6 Months Post-treatment or at Month 6 Post-treatment
Median time to first occurrence of treatment failure was not reached in this study.
Time frame: 6 months
Secondary
Number of Participants With Single Treatment Failures
Rates for all individual components of the primary endpoint 'treatment failure' until day 180: * Acute rejection diagnosed by biopsy (BPAR) * graft loss * death * loss to follow up * discontinuation from study drug due to lack of efficacy or toxicity (adverse events, every adverse event had to be interpreted as toxicity) * conversion to another dosing regimen (conversion to tacrolimus, prograf, etc.)
Time frame: 6 months
Population: Intent-to-treat population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Intensified Mycophenolate Sodium | Number of Participants With Single Treatment Failures | Death | 0 Participants |
| Intensified Mycophenolate Sodium | Number of Participants With Single Treatment Failures | Loss to follow-up | 1 Participants |
| Intensified Mycophenolate Sodium | Number of Participants With Single Treatment Failures | Biopsy-proven acute rejection | 2 Participants |
| Intensified Mycophenolate Sodium | Number of Participants With Single Treatment Failures | Discontinuation due to lack of efficacy / toxicity | 17 Participants |
| Intensified Mycophenolate Sodium | Number of Participants With Single Treatment Failures | Treated rejections | 13 Participants |
| Intensified Mycophenolate Sodium | Number of Participants With Single Treatment Failures | Conversion of doses | 8 Participants |
| Intensified Mycophenolate Sodium | Number of Participants With Single Treatment Failures | Graft loss | 1 Participants |
| Standard Mycophenolate Sodium | Number of Participants With Single Treatment Failures | Conversion of doses | 10 Participants |
| Standard Mycophenolate Sodium | Number of Participants With Single Treatment Failures | Graft loss | 2 Participants |
| Standard Mycophenolate Sodium | Number of Participants With Single Treatment Failures | Treated rejections | 24 Participants |
| Standard Mycophenolate Sodium | Number of Participants With Single Treatment Failures | Biopsy-proven acute rejection | 11 Participants |
| Standard Mycophenolate Sodium | Number of Participants With Single Treatment Failures | Death | 0 Participants |
| Standard Mycophenolate Sodium | Number of Participants With Single Treatment Failures | Loss to follow-up | 0 Participants |
| Standard Mycophenolate Sodium | Number of Participants With Single Treatment Failures | Discontinuation due to lack of efficacy / toxicity | 15 Participants |
Secondary
Rates of Events for Treated Acute Rejection, Death, Graft Loss, or Loss to Follow up on Day 28, Day 84, and Day 180
Due to a small number of events, median time to \<event\> was not reached.
Time frame: 6 months
Secondary
Renal Function as Measured by Glomerular Filtration Rate (GFR)
The Glomerular Filtration Rate (GFR) was calculated using the following formulas: * Cockcroft-Gault formula: calculation using the participant's age, gender, weight, and serum creatinine levels. * MDRD formula: calculation using the participant's age, gender, serum creatinine, urea nitrogen, and albumin levels.
Time frame: 6 months
Population: Intent-to-treat population for whom data was available. End of Study data was imputed using Last Observation Carried Forward (LOCF).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intensified Mycophenolate Sodium | Renal Function as Measured by Glomerular Filtration Rate (GFR) | Cockcroft-Gault formula: End of study [n=63, 65] | 52.4 ml/min | Standard Deviation 23.9 |
| Intensified Mycophenolate Sodium | Renal Function as Measured by Glomerular Filtration Rate (GFR) | MDRD formula: Baseline [n=44, 56] | 9.0 ml/min | Standard Deviation 3.9 |
| Intensified Mycophenolate Sodium | Renal Function as Measured by Glomerular Filtration Rate (GFR) | MDRD formula: End of study [n=61, 64] | 41.1 ml/min | Standard Deviation 17.1 |
| Intensified Mycophenolate Sodium | Renal Function as Measured by Glomerular Filtration Rate (GFR) | Cockcroft-Gault formula: Baseline [n=61, 65] | 12.1 ml/min | Standard Deviation 4.8 |
| Standard Mycophenolate Sodium | Renal Function as Measured by Glomerular Filtration Rate (GFR) | Cockcroft-Gault formula: Baseline [n=61, 65] | 12.0 ml/min | Standard Deviation 5 |
| Standard Mycophenolate Sodium | Renal Function as Measured by Glomerular Filtration Rate (GFR) | Cockcroft-Gault formula: End of study [n=63, 65] | 47.9 ml/min | Standard Deviation 27.1 |
| Standard Mycophenolate Sodium | Renal Function as Measured by Glomerular Filtration Rate (GFR) | MDRD formula: End of study [n=61, 64] | 40.6 ml/min | Standard Deviation 24.8 |
| Standard Mycophenolate Sodium | Renal Function as Measured by Glomerular Filtration Rate (GFR) | MDRD formula: Baseline [n=44, 56] | 9.4 ml/min | Standard Deviation 3.9 |
Secondary
Renal Function as Measured by Serum Creatinine
Time frame: 6 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Intensified Mycophenolate Sodium | Renal Function as Measured by Serum Creatinine | Baseline | 8.0 mg/dL | Standard Deviation 2.7 |
| Intensified Mycophenolate Sodium | Renal Function as Measured by Serum Creatinine | End of study | 2.2 mg/dL | Standard Deviation 1.5 |
| Standard Mycophenolate Sodium | Renal Function as Measured by Serum Creatinine | Baseline | 7.8 mg/dL | Standard Deviation 2.9 |
| Standard Mycophenolate Sodium | Renal Function as Measured by Serum Creatinine | End of study | 2.6 mg/dL | Standard Deviation 2.2 |
Secondary
Time to Event for the Composite Endpoint as Well as All Individual Components of That Endpoint Treatment Failure Including Clinical Rejections
Due to a small number of events, median time to \<event\> was not reached.
Time frame: 6 months