Kidney Transplantation
Conditions
Brief summary
This study will evaluate the correlation between the pharmacokinetic and pharmacodynamic parameters of CellCept in patients undergoing primary kidney transplantation, in order to assess the impact on clinical outcome and the risks of acute rejection. All patients will receive oral CellCept, 1g twice daily, and pharmacokinetic and pharmacodynamic parameters will be measured at weeks 2, 4, 12 and 24. The anticipated time on study treatment is 24 weeks.
Interventions
DRUGmycophenolate mofetil
1 g PO BID for 24 weeks
DRUGantibody induction
According to manufacturer recommendation
DRUGCyclosporine
According to manufacturer recommendation
DRUGcorticosteroid
According to manufacturer recommendation
Sponsors
Hoffmann-La Roche
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Adult patients, 18 to 65 years of age * Patients undergoing primary kidney transplantation
Exclusion criteria
* Recipients of multiple organ transplants * Prior therapy with CellCept * Presence or history of malignancies, except for successfully treated basal or squamous cell carcinoma of the skin * Active peptic ulcer or active serious digestive system disease that may affect the absorption of CellCept
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Acute Rejection | Day 1, Weeks 2, 4, 12, 24, and 28 | Diagnosis of acute rejection was suspected in any participant with an increase in serum creatinine greater than or equal to (≥) 25 percent (%). All suspected acute rejections were confirmed by biopsy. The start date of acute rejection was identified as the date of biopsy. |
| Time to Rejection | Day 1, Weeks 2, 4, 12, 24, and 28 | The mean time, in days, from the date of enrollment to date of biopsy confirming acute rejection. |
| Percentage of Participants With Biopsy-Proven Acute Rejection (BPAR) | Day 1, Weeks 2, 4, 12, 24, and 28 | BPAR was defined according to 1997 Banff Criteria as a biopsy Banff grade of IA, IB, IIA, IIB, or III. Grade IA was defined as significant interstitial infiltration with greater than (\>)25% of parenchyma affected, and foci of moderate tubulitis with \>4 mononuclear cells per tubular cross section or group of 10 tubular cells. Grade IB was defined as significant interstitial infiltration with \>25% parenchyma affected, and foci of severe tubulitis with \>10% mononuclear cells per tubular cross section or group of 10 tubular cells. Grade IIA was defined as mild to moderate intimal arteritis. Grade IIB was defined as severe intimal arteritis comprising \>25% of the luminal area. Grade III was defined as transmural arteritis and/or arterial fibrinoid changes and necrosis of medial smooth muscle cells. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Free MPA (mcg/mL) by Visit | Weeks 2, 4, 12, 24, safety follow-up (Week 28), and any unscheduled visits | Drug quantification of free MPA in the plasma was measured at T = 0, 40, and 120 mins. |
| MPA Area Under the Concentration - Time Curve From Time 0 to 12 Hours (AUC0-12) (mcg/mL) by Visit | Predose and 40 minutes and 2 hours postdose at Weeks 2, 4, 12, and 24, and at the Safety follow-up (Week 28) | The AUC0-12 of MPA was estimated on the validated limited sampling strategy, AUC (milligrams multiplied by height over liter \[mg.h/L\]) = 7.182 + 4.607 multiplied by (\*) concentration at 0 minutes (C0)+ 0.998 \* the concentration at 40 minutes (C0.67) + 2.149 \* the concentration at 120 minutes (C2). |
| Inosine MonoPhosphate DeHydrogenase (IMPDH) Activity by Visit and Timepoint | BL and Weeks 2, 4, 12, and 24, and safety follow-up (Week 28) and any unscheduled visits | IMPDH activity in peripheral blood mononuclear cells (PBMCs) was measured at 2 timepoints per visit, 0 and 120 minutes and presented in enzyme units. The unit of measure of enzyme activity is U. One U is defined as the amount of the enzyme that produces a certain amount of enzymatic activity that is, the amount that catalyzes the conversion of 1 micro mole of substrate per minute under pre-specified conditions (temperature, pH). |
| IMPDH Expression I by Visit and Timepoint | BL and Weeks 2, 4, 12, and 24, and safety follow-up (Week 28) and any unscheduled visits | IMPDH I gene expression was measured by real time polymerase chain reaction (QRT-PCR) based cytokine measurement of PBMCs at 2 timepoints per visit, 0 and 120 minutes and expressed as number of messenger ribonucleic acid (mRNA) copies per cell (copies/cell). |
| IMPDH Expression II by Visit and Timepoint | BL and Weeks 2, 4, 12, and 24, and safety follow-up (Week 28) and any unscheduled visits | IMPDH II gene expression was measured by QRT-PCR based cytokine measurement of PBMCs at 2 timepoints per visit, 0 and 120 minutes and expressed as number of mRNA copies/cell. |
| Interleukin 8 (IL-8) Expression by Visit and Timepoint | BL and Weeks 2, 4, 12, and 24, and safety follow-up (Week 28) and any unscheduled visits | IL-8 gene expression was measured by QRT-PCR based cytokine measurement of PBMCs at 2 timepoints per visit, 0 and 120 minutes and expressed as number of mRNA copies/cell. |
| Tumor Necrosis Factor (TNF) Expression by Visit and Timepoint | BL and Weeks 2, 4, 12, and 24, and safety follow-up (Week 28) and any unscheduled visits | TNF gene expression was measured by QRT-PCR based cytokine measurement of PBMCs at 2 timepoints per visit, 0 and 120 minutes and expressed as number of mRNA copies/cell. |
| Percentage of Participants With Infection | BL and Weeks 2, 4, 12, 24, and 28 (Safety Follow-Up) | Infections were graded according to the World Health Organization (WHO) worst grade observed. |
| Percentage of Participants With Gastrointestinal Toxicities | BL and Weeks 2, 4, 12, 24, and 28 (Safety Follow-up Visit) | Gastrointestinal adverse events (AEs) according to WHO worst grade observed. |
| Percentage of Participants With Hematologic Toxicity | BL and Weeks 2, 4, 12, 24, and 28 (Safety Follow-Up) | Hematological toxicities graded according to WHO worst grade observed (Grade 1=mild, Grade 2=moderate). |
| Spearman's Rank Correlation Coefficient Between MPA Levels and IMPDH Activity | BL and Weeks 2, 4, 12, and 24 | The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used. |
| Percentage of Participants With Graft Loss | Day 1, Weeks 2, 4, 12, 24, and 28 | An allograft was presumed to be lost if a participant started dialysis and was not able to subsequently be removed from dialysis. |
| Spearman's Rank Correlation Coefficient Between IMPDH I Expression and Free Fraction | BL and Weeks 2, 4, 12, and 24 | The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used. |
| Spearman's Rank Correlation Coefficient Between IMPDH II Expression and MPA Levels | BL and Weeks 2, 4, 12, and 24 | The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used. |
| Spearman's Rank Correlation Coefficient Between IMPDH II Expression and Free Fraction | BL and Weeks 2, 4, 12, and 24 | The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used. |
| Spearman's Rank Correlation Coefficient Between IMPDH Inhibition and Risk of Acute Rejection | BL and Weeks 2, 4, 12, and 24 | The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used. |
| Spearman's Rank Correlation Coefficient Between IMPDH Expression and Risk of Infection | BL and Weeks 2, 4, 12, and 24 | The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used. |
| Spearman's Rank Correlation Coefficient Between IMPDH Expression and Risk of Hematologic Toxicity | BL and Weeks 2, 4, 12, and 24 | The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used. |
| Spearman's Rank Correlation Coefficient Between IMPDH Expression and Risk of Gastrointestinal Toxicity | BL and Weeks 2, 4, 12, and 24 | The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used. |
| Spearman's Rank Correlation Coefficient Between MPA Levels and Risk of Infection | BL and Weeks 2, 4, 12, and 24 | The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used. |
| Spearman's Rank Correlation Coefficient Between MPA Levels and Risk of Hematologic Toxicity | BL and Weeks 2, 4, 12, and 24 | The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used. |
| Spearman's Rank Correlation Coefficient Between MPA Levels and Risk of Gastrointestinal Toxicity | BL and Weeks 2, 4, 12, and 24 | The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used. |
| Spearman's Rank Correlation Coefficient Between IMPDH I Expression and MPA Levels | BL and Weeks 2, 4, 12, and 24 | The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used. |
| Percentage of Participants Surviving | Day 1, Weeks 2, 4, 12, 24, and 28 | — |
| Total Mycophenolate Acid (MPA) by Visit and Timepoint | Weeks 2, 4, 12, 24, and 28 (Safety Follow-Up Visit), and any unscheduled visits | Drug quantification of total MPA (micrograms per milliliter \[mcg/mL\]) in the plasma was measured at time (T) = 0 minutes (min), 40 mins, and 120 mins. |
Countries
Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MMF Monotherapy Participants received an initial dose of MMF 1 g, PO, BID, started within 5 days of transplant, for up to 24 weeks. MMF dose could be titrated to a maximum daily dose of 2 g (minimum daily dose was 1 g). Participants also received concurrent antibody induction, cyclosporine, and corticosteroids as needed according to center's practice. | 45 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 5 |
| Overall Study | Death | 1 |
| Overall Study | Graft loss | 1 |
| Overall Study | Other | 2 |
| Overall Study | Protocol Violation | 3 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | MMF Monotherapy |
|---|---|
| Age, Continuous | 46.60 years STANDARD_DEVIATION 9.92 |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 43 / 45 |
| serious Total, serious adverse events | 20 / 45 |
Outcome results
Primary
Percentage of Participants With Acute Rejection
Diagnosis of acute rejection was suspected in any participant with an increase in serum creatinine greater than or equal to (≥) 25 percent (%). All suspected acute rejections were confirmed by biopsy. The start date of acute rejection was identified as the date of biopsy.
Time frame: Day 1, Weeks 2, 4, 12, 24, and 28
Population: Intent-to-treat (ITT) population: all eligible participants who had at least baseline (BL) and 1 assessment of pharmacokinetics (PK) and pharmacodynamics (PD). Acute rejection was analyzed in any participant with an increase in serum creatinine of 25%.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MMF Monotherapy | Percentage of Participants With Acute Rejection | 9.1 percentage of participants |
Primary
Percentage of Participants With Biopsy-Proven Acute Rejection (BPAR)
BPAR was defined according to 1997 Banff Criteria as a biopsy Banff grade of IA, IB, IIA, IIB, or III. Grade IA was defined as significant interstitial infiltration with greater than (\>)25% of parenchyma affected, and foci of moderate tubulitis with \>4 mononuclear cells per tubular cross section or group of 10 tubular cells. Grade IB was defined as significant interstitial infiltration with \>25% parenchyma affected, and foci of severe tubulitis with \>10% mononuclear cells per tubular cross section or group of 10 tubular cells. Grade IIA was defined as mild to moderate intimal arteritis. Grade IIB was defined as severe intimal arteritis comprising \>25% of the luminal area. Grade III was defined as transmural arteritis and/or arterial fibrinoid changes and necrosis of medial smooth muscle cells.
Time frame: Day 1, Weeks 2, 4, 12, 24, and 28
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MMF Monotherapy | Percentage of Participants With Biopsy-Proven Acute Rejection (BPAR) | 4.5 percentage of participants |
Primary
Time to Rejection
The mean time, in days, from the date of enrollment to date of biopsy confirming acute rejection.
Time frame: Day 1, Weeks 2, 4, 12, 24, and 28
Population: ITT population; only participants with acute or biopsy-proven rejection were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MMF Monotherapy | Time to Rejection | 23.67 days | Standard Deviation 21.44 |
Secondary
Free MPA (mcg/mL) by Visit
Drug quantification of free MPA in the plasma was measured at T = 0, 40, and 120 mins.
Time frame: Weeks 2, 4, 12, 24, safety follow-up (Week 28), and any unscheduled visits
Population: ITT population; n=number of samples analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MMF Monotherapy | Free MPA (mcg/mL) by Visit | T=120, unscheduled visit (n=7) | 0.07 mcg/mL | Standard Deviation 0.03 |
| MMF Monotherapy | Free MPA (mcg/mL) by Visit | T=40, Week 2 (n=41) | 0.11 mcg/mL | Standard Deviation 0.09 |
| MMF Monotherapy | Free MPA (mcg/mL) by Visit | T=40, Week 4 (n=42) | 0.11 mcg/mL | Standard Deviation 0.07 |
| MMF Monotherapy | Free MPA (mcg/mL) by Visit | T=0, Week 2 (n=40) | 0.03 mcg/mL | Standard Deviation 0.03 |
| MMF Monotherapy | Free MPA (mcg/mL) by Visit | T=0, Week 4 (n=39) | 0.04 mcg/mL | Standard Deviation 0.03 |
| MMF Monotherapy | Free MPA (mcg/mL) by Visit | T=0, Week 12 (n=33) | 0.03 mcg/mL | Standard Deviation 0.02 |
| MMF Monotherapy | Free MPA (mcg/mL) by Visit | T=0, Week 24 (n=32) | 0.03 mcg/mL | Standard Deviation 0.02 |
| MMF Monotherapy | Free MPA (mcg/mL) by Visit | T=0, safety follow-up (n=3) | 0.01 mcg/mL | Standard Deviation 0.01 |
| MMF Monotherapy | Free MPA (mcg/mL) by Visit | T=0, unscheduled visit (n=7) | 0.04 mcg/mL | Standard Deviation 0.03 |
| MMF Monotherapy | Free MPA (mcg/mL) by Visit | T=0, overall mean value (n=154) | 0.03 mcg/mL | Standard Deviation 0.03 |
| MMF Monotherapy | Free MPA (mcg/mL) by Visit | T=40, Week 12 (n=35) | 0.11 mcg/mL | Standard Deviation 0.06 |
| MMF Monotherapy | Free MPA (mcg/mL) by Visit | T=40, Week 24 (n=35) | 0.38 mcg/mL | Standard Deviation 1.35 |
| MMF Monotherapy | Free MPA (mcg/mL) by Visit | T=40, safety follow-up (n=3) | 0.06 mcg/mL | Standard Deviation 0.02 |
| MMF Monotherapy | Free MPA (mcg/mL) by Visit | T=40, unscheduled visit (n=7) | 0.09 mcg/mL | Standard Deviation 0.07 |
| MMF Monotherapy | Free MPA (mcg/mL) by Visit | T=40, overall mean value (n=163) | 0.17 mcg/mL | Standard Deviation 0.63 |
| MMF Monotherapy | Free MPA (mcg/mL) by Visit | T=120, Week 2 (n=43) | 0.11 mcg/mL | Standard Deviation 0.07 |
| MMF Monotherapy | Free MPA (mcg/mL) by Visit | T=120, Week 4 (n=42) | 0.11 mcg/mL | Standard Deviation 0.07 |
| MMF Monotherapy | Free MPA (mcg/mL) by Visit | T=120, Week 12 (n=35) | 0.16 mcg/mL | Standard Deviation 0.36 |
| MMF Monotherapy | Free MPA (mcg/mL) by Visit | T=120, Week 24 (n=35) | 0.10 mcg/mL | Standard Deviation 0.06 |
| MMF Monotherapy | Free MPA (mcg/mL) by Visit | T=120, safety follow-up (n=3) | 0.10 mcg/mL | Standard Deviation 0.03 |
| MMF Monotherapy | Free MPA (mcg/mL) by Visit | T=120, overall mean value (n=165) | 0.12 mcg/mL | Standard Deviation 0.18 |
Secondary
IMPDH Expression I by Visit and Timepoint
IMPDH I gene expression was measured by real time polymerase chain reaction (QRT-PCR) based cytokine measurement of PBMCs at 2 timepoints per visit, 0 and 120 minutes and expressed as number of messenger ribonucleic acid (mRNA) copies per cell (copies/cell).
Time frame: BL and Weeks 2, 4, 12, and 24, and safety follow-up (Week 28) and any unscheduled visits
Population: ITT population; n=number of samples analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MMF Monotherapy | IMPDH Expression I by Visit and Timepoint | T=120, BL (n=0) | 0 number of mRNA copies/cell | Standard Deviation 0 |
| MMF Monotherapy | IMPDH Expression I by Visit and Timepoint | T=0, BL (n=44) | 2.32 number of mRNA copies/cell | Standard Deviation 3.02 |
| MMF Monotherapy | IMPDH Expression I by Visit and Timepoint | T=0, Week 2 (n=41) | 32.29 number of mRNA copies/cell | Standard Deviation 188.29 |
| MMF Monotherapy | IMPDH Expression I by Visit and Timepoint | T=0, Week 4 (n=42) | 3.16 number of mRNA copies/cell | Standard Deviation 8.59 |
| MMF Monotherapy | IMPDH Expression I by Visit and Timepoint | T=0, Week 12 (n=34) | 4.10 number of mRNA copies/cell | Standard Deviation 15.09 |
| MMF Monotherapy | IMPDH Expression I by Visit and Timepoint | T=0, Week 24 (n=34) | 1.95 number of mRNA copies/cell | Standard Deviation 2.94 |
| MMF Monotherapy | IMPDH Expression I by Visit and Timepoint | T=0, safety follow-up (n=3) | 11803.48 number of mRNA copies/cell | Standard Deviation 20432.48 |
| MMF Monotherapy | IMPDH Expression I by Visit and Timepoint | T=0, unscheduled visit (n=7) | 4.00 number of mRNA copies/cell | Standard Deviation 3.84 |
| MMF Monotherapy | IMPDH Expression I by Visit and Timepoint | T=0, mean value (n=205) | 181.48 number of mRNA copies/cell | Standard Deviation 2473.05 |
| MMF Monotherapy | IMPDH Expression I by Visit and Timepoint | T=120, Week 2 (n=43) | 4146.17 number of mRNA copies/cell | Standard Deviation 14891.57 |
| MMF Monotherapy | IMPDH Expression I by Visit and Timepoint | T=120, Week 4 (n=42) | 1692.11 number of mRNA copies/cell | Standard Deviation 6690.21 |
| MMF Monotherapy | IMPDH Expression I by Visit and Timepoint | T=120, Week 12 (n=35) | 1556.06 number of mRNA copies/cell | Standard Deviation 5856.17 |
| MMF Monotherapy | IMPDH Expression I by Visit and Timepoint | T=120, Week 24 (n=34) | 3.02 number of mRNA copies/cell | Standard Deviation 7.53 |
| MMF Monotherapy | IMPDH Expression I by Visit and Timepoint | T=120, safety follow-up (n=3) | 107.30 number of mRNA copies/cell | Standard Deviation 179.38 |
| MMF Monotherapy | IMPDH Expression I by Visit and Timepoint | T=120, unscheduled visit (n=7) | 1038.52 number of mRNA copies/cell | Standard Deviation 1781.89 |
| MMF Monotherapy | IMPDH Expression I by Visit and Timepoint | T=120, mean value (n=164) | 1899.45 number of mRNA copies/cell | Standard Deviation 8824.89 |
Secondary
IMPDH Expression II by Visit and Timepoint
IMPDH II gene expression was measured by QRT-PCR based cytokine measurement of PBMCs at 2 timepoints per visit, 0 and 120 minutes and expressed as number of mRNA copies/cell.
Time frame: BL and Weeks 2, 4, 12, and 24, and safety follow-up (Week 28) and any unscheduled visits
Population: ITT population; n=number of samples analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MMF Monotherapy | IMPDH Expression II by Visit and Timepoint | T=0, BL (n=44) | 115.33 number of mRNA copies/cell | Standard Deviation 19.81 |
| MMF Monotherapy | IMPDH Expression II by Visit and Timepoint | T=0, Week 2 (n=41) | 113.43 number of mRNA copies/cell | Standard Deviation 21.67 |
| MMF Monotherapy | IMPDH Expression II by Visit and Timepoint | T=0, Week 4 (n=42) | 117.16 number of mRNA copies/cell | Standard Deviation 30.72 |
| MMF Monotherapy | IMPDH Expression II by Visit and Timepoint | T=0, Week 12 (n=34) | 112.43 number of mRNA copies/cell | Standard Deviation 24.57 |
| MMF Monotherapy | IMPDH Expression II by Visit and Timepoint | T=0, Week 24 (n=34) | 114.21 number of mRNA copies/cell | Standard Deviation 19.79 |
| MMF Monotherapy | IMPDH Expression II by Visit and Timepoint | T=0, safety follow-up (n=3) | 123.86 number of mRNA copies/cell | Standard Deviation 37.61 |
| MMF Monotherapy | IMPDH Expression II by Visit and Timepoint | T=0, unscheduled visit (n=7) | 116.57 number of mRNA copies/cell | Standard Deviation 19.25 |
| MMF Monotherapy | IMPDH Expression II by Visit and Timepoint | T=0, mean value (n=205) | 114.82 number of mRNA copies/cell | Standard Deviation 23.54 |
| MMF Monotherapy | IMPDH Expression II by Visit and Timepoint | T=120, BL (n=0) | 0 number of mRNA copies/cell | Standard Deviation 0 |
| MMF Monotherapy | IMPDH Expression II by Visit and Timepoint | T=120, Week 2 (n=43) | 304.64 number of mRNA copies/cell | Standard Deviation 309.26 |
| MMF Monotherapy | IMPDH Expression II by Visit and Timepoint | T=120, Week 4 (n=42) | 148.32 number of mRNA copies/cell | Standard Deviation 206.39 |
| MMF Monotherapy | IMPDH Expression II by Visit and Timepoint | T=120, Week 12 (n=35) | 143.11 number of mRNA copies/cell | Standard Deviation 82.95 |
| MMF Monotherapy | IMPDH Expression II by Visit and Timepoint | T=120, Week 24 (n=34) | 109.00 number of mRNA copies/cell | Standard Deviation 22.81 |
| MMF Monotherapy | IMPDH Expression II by Visit and Timepoint | T=120, safety follow-up (n=3) | 140.51 number of mRNA copies/cell | Standard Deviation 42.37 |
| MMF Monotherapy | IMPDH Expression II by Visit and Timepoint | T=120, unscheduled visit (n=7) | 167.19 number of mRNA copies/cell | Standard Deviation 155.73 |
| MMF Monotherapy | IMPDH Expression II by Visit and Timepoint | T=120, mean value (n=164) | 180.71 number of mRNA copies/cell | Standard Deviation 208.68 |
Secondary
Inosine MonoPhosphate DeHydrogenase (IMPDH) Activity by Visit and Timepoint
IMPDH activity in peripheral blood mononuclear cells (PBMCs) was measured at 2 timepoints per visit, 0 and 120 minutes and presented in enzyme units. The unit of measure of enzyme activity is U. One U is defined as the amount of the enzyme that produces a certain amount of enzymatic activity that is, the amount that catalyzes the conversion of 1 micro mole of substrate per minute under pre-specified conditions (temperature, pH).
Time frame: BL and Weeks 2, 4, 12, and 24, and safety follow-up (Week 28) and any unscheduled visits
Population: ITT population; n=number of samples analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MMF Monotherapy | Inosine MonoPhosphate DeHydrogenase (IMPDH) Activity by Visit and Timepoint | T=0, BL (n=44) | 5.01 enzyme units | Standard Deviation 5.17 |
| MMF Monotherapy | Inosine MonoPhosphate DeHydrogenase (IMPDH) Activity by Visit and Timepoint | T=0, Week 2 (n=42) | 3.96 enzyme units | Standard Deviation 3.58 |
| MMF Monotherapy | Inosine MonoPhosphate DeHydrogenase (IMPDH) Activity by Visit and Timepoint | T=0, Week 4 (n=42) | 3.89 enzyme units | Standard Deviation 2.36 |
| MMF Monotherapy | Inosine MonoPhosphate DeHydrogenase (IMPDH) Activity by Visit and Timepoint | T=0, Week 12 (n=35) | 6.74 enzyme units | Standard Deviation 11.79 |
| MMF Monotherapy | Inosine MonoPhosphate DeHydrogenase (IMPDH) Activity by Visit and Timepoint | T=0, Week 24 (n=34) | 9.58 enzyme units | Standard Deviation 10.81 |
| MMF Monotherapy | Inosine MonoPhosphate DeHydrogenase (IMPDH) Activity by Visit and Timepoint | T=0, safety follow-up (n=0) | 0 enzyme units | Standard Deviation 0 |
| MMF Monotherapy | Inosine MonoPhosphate DeHydrogenase (IMPDH) Activity by Visit and Timepoint | T=0, unscheduled visit (n=7) | 6.00 enzyme units | Standard Deviation 6.12 |
| MMF Monotherapy | Inosine MonoPhosphate DeHydrogenase (IMPDH) Activity by Visit and Timepoint | T=0, mean value (n=204) | 5.65 enzyme units | Standard Deviation 7.54 |
| MMF Monotherapy | Inosine MonoPhosphate DeHydrogenase (IMPDH) Activity by Visit and Timepoint | T=120, BL (n=0) | 0 enzyme units | Standard Deviation 0 |
| MMF Monotherapy | Inosine MonoPhosphate DeHydrogenase (IMPDH) Activity by Visit and Timepoint | T=120, Week 2 (n=42) | 3.06 enzyme units | Standard Deviation 3.42 |
| MMF Monotherapy | Inosine MonoPhosphate DeHydrogenase (IMPDH) Activity by Visit and Timepoint | T=120, Week 4 (n=42) | 3.10 enzyme units | Standard Deviation 2.66 |
| MMF Monotherapy | Inosine MonoPhosphate DeHydrogenase (IMPDH) Activity by Visit and Timepoint | T=120, Week 12 (n=35) | 3.75 enzyme units | Standard Deviation 5.02 |
| MMF Monotherapy | Inosine MonoPhosphate DeHydrogenase (IMPDH) Activity by Visit and Timepoint | T=120, Week 24 (n=34) | 6.39 enzyme units | Standard Deviation 6.14 |
| MMF Monotherapy | Inosine MonoPhosphate DeHydrogenase (IMPDH) Activity by Visit and Timepoint | T=120, safety follow-up (n=0) | 0 enzyme units | Standard Deviation 0 |
| MMF Monotherapy | Inosine MonoPhosphate DeHydrogenase (IMPDH) Activity by Visit and Timepoint | T=120, unscheduled visit (n=7) | 3.89 enzyme units | Standard Deviation 1.82 |
| MMF Monotherapy | Inosine MonoPhosphate DeHydrogenase (IMPDH) Activity by Visit and Timepoint | T=120, mean value (n=160) | 3.97 enzyme units | Standard Deviation 4.46 |
Secondary
Interleukin 8 (IL-8) Expression by Visit and Timepoint
IL-8 gene expression was measured by QRT-PCR based cytokine measurement of PBMCs at 2 timepoints per visit, 0 and 120 minutes and expressed as number of mRNA copies/cell.
Time frame: BL and Weeks 2, 4, 12, and 24, and safety follow-up (Week 28) and any unscheduled visits
Population: ITT population; n=number of samples analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MMF Monotherapy | Interleukin 8 (IL-8) Expression by Visit and Timepoint | T=0, BL (n=44) | 4532.72 number of mRNA copies/cell | Standard Deviation 11598.93 |
| MMF Monotherapy | Interleukin 8 (IL-8) Expression by Visit and Timepoint | T=0, Week 2 (n=41) | 29960.41 number of mRNA copies/cell | Standard Deviation 128979.24 |
| MMF Monotherapy | Interleukin 8 (IL-8) Expression by Visit and Timepoint | T=0, Week 4 (n=42) | 54101.30 number of mRNA copies/cell | Standard Deviation 262581.32 |
| MMF Monotherapy | Interleukin 8 (IL-8) Expression by Visit and Timepoint | T=0, Week 12 (n=34) | 1829.87 number of mRNA copies/cell | Standard Deviation 6411.17 |
| MMF Monotherapy | Interleukin 8 (IL-8) Expression by Visit and Timepoint | T=0, Week 24 (n=34) | 10391.60 number of mRNA copies/cell | Standard Deviation 42574.52 |
| MMF Monotherapy | Interleukin 8 (IL-8) Expression by Visit and Timepoint | T=0, safety follow-up (n=3) | 1254.29 number of mRNA copies/cell | Standard Deviation 1150.4 |
| MMF Monotherapy | Interleukin 8 (IL-8) Expression by Visit and Timepoint | T=0, unscheduled visit (n=7) | 19148.94 number of mRNA copies/cell | Standard Deviation 49991.25 |
| MMF Monotherapy | Interleukin 8 (IL-8) Expression by Visit and Timepoint | T=0, mean value (n=205) | 20748.32 number of mRNA copies/cell | Standard Deviation 1333817.1 |
| MMF Monotherapy | Interleukin 8 (IL-8) Expression by Visit and Timepoint | T=120, BL (n=0) | 0.0 number of mRNA copies/cell | Standard Deviation 0 |
| MMF Monotherapy | Interleukin 8 (IL-8) Expression by Visit and Timepoint | T=120, Week 2 (n=43) | 1028.93 number of mRNA copies/cell | Standard Deviation 4210.43 |
| MMF Monotherapy | Interleukin 8 (IL-8) Expression by Visit and Timepoint | T=120, Week 4 (n=42) | 21227.11 number of mRNA copies/cell | Standard Deviation 103517.73 |
| MMF Monotherapy | Interleukin 8 (IL-8) Expression by Visit and Timepoint | T=120, Week 12 (n=35) | 12022.83 number of mRNA copies/cell | Standard Deviation 63647.48 |
| MMF Monotherapy | Interleukin 8 (IL-8) Expression by Visit and Timepoint | T=120, Week 24 (n=34) | 9418.65 number of mRNA copies/cell | Standard Deviation 29084 |
| MMF Monotherapy | Interleukin 8 (IL-8) Expression by Visit and Timepoint | T=120, safety follow-up (n=3) | 397887.30 number of mRNA copies/cell | Standard Deviation 688477.81 |
| MMF Monotherapy | Interleukin 8 (IL-8) Expression by Visit and Timepoint | T=120, unscheduled visit (n=7) | 220.14 number of mRNA copies/cell | Standard Deviation 457.26 |
| MMF Monotherapy | Interleukin 8 (IL-8) Expression by Visit and Timepoint | T=120, mean value (n=164) | 17512.31 number of mRNA copies/cell | Standard Deviation 110920.39 |
Secondary
MPA Area Under the Concentration - Time Curve From Time 0 to 12 Hours (AUC0-12) (mcg/mL) by Visit
The AUC0-12 of MPA was estimated on the validated limited sampling strategy, AUC (milligrams multiplied by height over liter \[mg.h/L\]) = 7.182 + 4.607 multiplied by (\*) concentration at 0 minutes (C0)+ 0.998 \* the concentration at 40 minutes (C0.67) + 2.149 \* the concentration at 120 minutes (C2).
Time frame: Predose and 40 minutes and 2 hours postdose at Weeks 2, 4, 12, and 24, and at the Safety follow-up (Week 28)
Population: ITT population; n=number of participants assessed for the specified parameter at a given visit.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MMF Monotherapy | MPA Area Under the Concentration - Time Curve From Time 0 to 12 Hours (AUC0-12) (mcg/mL) by Visit | Week 24 (n=35) | 39.8 mcg*hr/mL | Standard Deviation 17 |
| MMF Monotherapy | MPA Area Under the Concentration - Time Curve From Time 0 to 12 Hours (AUC0-12) (mcg/mL) by Visit | Week 2 (n=41) | 38.3 mcg*hr/mL | Standard Deviation 17.9 |
| MMF Monotherapy | MPA Area Under the Concentration - Time Curve From Time 0 to 12 Hours (AUC0-12) (mcg/mL) by Visit | Week 4 (n=42) | 39.7 mcg*hr/mL | Standard Deviation 17.4 |
| MMF Monotherapy | MPA Area Under the Concentration - Time Curve From Time 0 to 12 Hours (AUC0-12) (mcg/mL) by Visit | Week 12 (n=35) | 39.7 mcg*hr/mL | Standard Deviation 16.5 |
| MMF Monotherapy | MPA Area Under the Concentration - Time Curve From Time 0 to 12 Hours (AUC0-12) (mcg/mL) by Visit | Follow-up (n=3) | 29.7 mcg*hr/mL | Standard Deviation 3.7 |
Secondary
Percentage of Participants Surviving
Time frame: Day 1, Weeks 2, 4, 12, 24, and 28
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MMF Monotherapy | Percentage of Participants Surviving | 97.7 percentage of participants |
Secondary
Percentage of Participants With Gastrointestinal Toxicities
Gastrointestinal adverse events (AEs) according to WHO worst grade observed.
Time frame: BL and Weeks 2, 4, 12, 24, and 28 (Safety Follow-up Visit)
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MMF Monotherapy | Percentage of Participants With Gastrointestinal Toxicities | Abdominal pain (moderate) | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Gastrointestinal Toxicities | Abdominal pain (severe) | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Gastrointestinal Toxicities | Anal fissure (mild) | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Gastrointestinal Toxicities | Diarrhoea (mild) | 4.44 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Gastrointestinal Toxicities | Diarrhoea (moderate) | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Gastrointestinal Toxicities | Diarrhoea (severe) | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Gastrointestinal Toxicities | Dyspepsia (mild) | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Gastrointestinal Toxicities | Gastritis (moderate) | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Gastrointestinal Toxicities | Gastritis erosive (moderate) | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Gastrointestinal Toxicities | Gingival hyperplasia (mild) | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Gastrointestinal Toxicities | Haemorrhoids (mild) | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Gastrointestinal Toxicities | Intra-abdominal haematoma (mild) | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Gastrointestinal Toxicities | Nausea (moderate) | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Gastrointestinal Toxicities | Stomatitis (mild) | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Gastrointestinal Toxicities | Vomiting (mild) | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Gastrointestinal Toxicities | Vomiting (moderate) | 4.44 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Gastrointestinal Toxicities | Vomiting (severe) | 4.44 percentage of participants |
Secondary
Percentage of Participants With Graft Loss
An allograft was presumed to be lost if a participant started dialysis and was not able to subsequently be removed from dialysis.
Time frame: Day 1, Weeks 2, 4, 12, 24, and 28
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MMF Monotherapy | Percentage of Participants With Graft Loss | 2.3 percentage of participants |
Secondary
Percentage of Participants With Hematologic Toxicity
Hematological toxicities graded according to WHO worst grade observed (Grade 1=mild, Grade 2=moderate).
Time frame: BL and Weeks 2, 4, 12, 24, and 28 (Safety Follow-Up)
Population: Safety population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MMF Monotherapy | Percentage of Participants With Hematologic Toxicity | Grade 2 blood urea nitrogen increased | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Hematologic Toxicity | Grade 1 hemoglobin decreased | 13.33 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Hematologic Toxicity | Grade 1 leukocytes decreased | 11.11 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Hematologic Toxicity | Grade 2 leukocytes decreased | 8.89 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Hematologic Toxicity | Grade 1 granulocytes decreased | 6.67 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Hematologic Toxicity | Grade 2 granulocytes decreased | 6.67 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Hematologic Toxicity | Grade 1 platelets decreased | 6.67 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Hematologic Toxicity | Grade 1 bilirubin increased | 4.44 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Hematologic Toxicity | Grade 2 bilirubin increased | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Hematologic Toxicity | Grade 1 hypoglycemia | 4.44 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Hematologic Toxicity | Grade 1 alkaline phosphatase increased | 13.33 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Hematologic Toxicity | Grade 2 alkaline phosphatase increased | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Hematologic Toxicity | Grade 1 aspartate aminotransferase increased | 6.67 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Hematologic Toxicity | Grade 1 alanine aminotransferase increased | 8.89 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Hematologic Toxicity | Grade 2 alanine aminotransferase increased | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Hematologic Toxicity | Grade 1 cholesterol increased | 26.67 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Hematologic Toxicity | Grade 2 cholesterol increased | 8.89 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Hematologic Toxicity | Grade 1 triglycerides increased | 24.44 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Hematologic Toxicity | Grade 2 triglycerides increased | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Hematologic Toxicity | Grade 1 blood urea nitrogen increased | 2.22 percentage of participants |
Secondary
Percentage of Participants With Infection
Infections were graded according to the World Health Organization (WHO) worst grade observed.
Time frame: BL and Weeks 2, 4, 12, 24, and 28 (Safety Follow-Up)
Population: Safety population: all enrolled participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MMF Monotherapy | Percentage of Participants With Infection | CMV viraemia (mild) | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Infection | Acarodermatitis (mild) | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Infection | Bronchitis (moderate) | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Infection | Cytomegalovirus (CMV) infection (mild) | 13.33 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Infection | CMV infection (moderate) | 8.89 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Infection | CMV infection (severe) | 4.44 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Infection | Gastroenteritis proteus (severe) | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Infection | Gastrointestinal infection (severe) | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Infection | Legionella infection (life-threatening) | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Infection | Oral herpes (mild) | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Infection | Sepsis (life-threatening) | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Infection | Tracheitis (mild) | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Infection | Urethritis (mild) | 2.22 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Infection | Urinary tract infection (mild) | 28.89 percentage of participants |
| MMF Monotherapy | Percentage of Participants With Infection | Urinary tract infection (moderate) | 2.22 percentage of participants |
Secondary
Spearman's Rank Correlation Coefficient Between IMPDH Expression and Risk of Gastrointestinal Toxicity
The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used.
Time frame: BL and Weeks 2, 4, 12, and 24
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between IMPDH Expression and Risk of Gastrointestinal Toxicity | IMPDH I expression (n=334) | 0.082 correlation coefficient |
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between IMPDH Expression and Risk of Gastrointestinal Toxicity | IMPDH II expression (n=351) | 0.030 correlation coefficient |
p-value: 0.1328ANOVA
p-value: 0.576ANOVA
Secondary
Spearman's Rank Correlation Coefficient Between IMPDH Expression and Risk of Hematologic Toxicity
The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used.
Time frame: BL and Weeks 2, 4, 12, and 24
Population: ITT population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between IMPDH Expression and Risk of Hematologic Toxicity | IMPDH I expression (n=334) | -0.116 correlation coefficient |
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between IMPDH Expression and Risk of Hematologic Toxicity | IMPDH II expression (n=351) | -0.004 correlation coefficient |
p-value: 0.0316ANOVA
p-value: 0.944ANOVA
Secondary
Spearman's Rank Correlation Coefficient Between IMPDH Expression and Risk of Infection
The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used.
Time frame: BL and Weeks 2, 4, 12, and 24
Population: ITT population; n=number of samples analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between IMPDH Expression and Risk of Infection | IMPDH I expression (n=334) | 0.045 correlation coefficient |
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between IMPDH Expression and Risk of Infection | IMPDH II expression (n=351) | 0.047 correlation coefficient |
p-value: 0.413ANOVA
p-value: 0.3823ANOVA
Secondary
Spearman's Rank Correlation Coefficient Between IMPDH I Expression and Free Fraction
The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used.
Time frame: BL and Weeks 2, 4, 12, and 24
Population: ITT population; n=number of samples analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between IMPDH I Expression and Free Fraction | p Free fraction, T=0 (n=140) | 0.047 correlation coefficient |
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between IMPDH I Expression and Free Fraction | p Free fraction, T=120 (n=143) | 0.080 correlation coefficient |
p-value: 0.5796ANOVA
p-value: 0.3428ANOVA
Secondary
Spearman's Rank Correlation Coefficient Between IMPDH I Expression and MPA Levels
The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used.
Time frame: BL and Weeks 2, 4, 12, and 24
Population: ITT population; n=number of samples analyzed
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between IMPDH I Expression and MPA Levels | Free MPA, T=0 (n=141) | 0.073 correlation coefficient |
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between IMPDH I Expression and MPA Levels | Free MPA, T=120 (n=143) | -0.024 correlation coefficient |
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between IMPDH I Expression and MPA Levels | Total MPA, T=0 (n=147) | 0.037 correlation coefficient |
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between IMPDH I Expression and MPA Levels | Total MPA, T=120 (n=143) | -0.140 correlation coefficient |
p-value: 0.3892ANOVA
p-value: 0.6564ANOVA
p-value: 0.7772ANOVA
p-value: 0.0958ANOVA
Secondary
Spearman's Rank Correlation Coefficient Between IMPDH II Expression and Free Fraction
The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used.
Time frame: BL and Weeks 2, 4, 12, and 24
Population: ITT population; n=number of samples analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between IMPDH II Expression and Free Fraction | p Free fraction, T=0 (n=144) | -0.027 correlation coefficient |
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between IMPDH II Expression and Free Fraction | p Free fraction, T=120 (n=153) | 0.015 correlation coefficient |
p-value: 0.7455ANOVA
p-value: 0.8504ANOVA
Secondary
Spearman's Rank Correlation Coefficient Between IMPDH II Expression and MPA Levels
The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used.
Time frame: BL and Weeks 2, 4, 12, and 24
Population: ITT population; n=number of samples analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between IMPDH II Expression and MPA Levels | Free MPA, T=0 (n=145) | 0.007 correlation coefficient |
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between IMPDH II Expression and MPA Levels | Free MPA, T=120 (n=153) | 0.073 correlation coefficient |
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between IMPDH II Expression and MPA Levels | Total MPA, T=0 (n=152) | -0.001 correlation coefficient |
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between IMPDH II Expression and MPA Levels | Total MPA, T=120 (n=153) | 0.084 correlation coefficient |
p-value: 0.9372ANOVA
p-value: 0.9904ANOVA
p-value: 0.3658ANOVA
p-value: 0.2987ANOVA
Secondary
Spearman's Rank Correlation Coefficient Between IMPDH Inhibition and Risk of Acute Rejection
The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used.
Time frame: BL and Weeks 2, 4, 12, and 24
Population: ITT population; n=number of samples analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between IMPDH Inhibition and Risk of Acute Rejection | IMPDH I expression, T=0 (n=189) | 0.030 correlation coefficient |
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between IMPDH Inhibition and Risk of Acute Rejection | IMPDH I expression T=120 (n=145) | 0.083 correlation coefficient |
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between IMPDH Inhibition and Risk of Acute Rejection | IMPDH II expression, T=0 (n=196) | -0.062 correlation coefficient |
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between IMPDH Inhibition and Risk of Acute Rejection | IMPDH II expression (T=120, n=155) | -0.010 correlation coefficient |
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between IMPDH Inhibition and Risk of Acute Rejection | MPDH Activity, T=0 (n=198) | -0.121 correlation coefficient |
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between IMPDH Inhibition and Risk of Acute Rejection | IMPDH Activity, T=120 (n=155) | -0.004 correlation coefficient |
p-value: 0.6847ANOVA
p-value: 0.3184ANOVA
p-value: 0.3862ANOVA
p-value: 0.904ANOVA
p-value: 0.0907ANOVA
p-value: 0.963ANOVA
Secondary
Spearman's Rank Correlation Coefficient Between MPA Levels and IMPDH Activity
The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used.
Time frame: BL and Weeks 2, 4, 12, and 24
Population: ITT population; n=number of samples analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between MPA Levels and IMPDH Activity | Free MPA, T=0 (n=144) | 0.063 correlation coefficient |
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between MPA Levels and IMPDH Activity | Free MPA, T=120 (n=153) | 0.028 correlation coefficient |
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between MPA Levels and IMPDH Activity | Total MPA, T=0 (n=152) | 0.034 correlation coefficient |
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between MPA Levels and IMPDH Activity | Total MPA, T=120 (n=153) | -0.050 correlation coefficient |
p-value: 0.4505ANOVA
p-value: 0.7322ANOVA
p-value: 0.6798ANOVA
p-value: 0.541ANOVA
Secondary
Spearman's Rank Correlation Coefficient Between MPA Levels and Risk of Gastrointestinal Toxicity
The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used.
Time frame: BL and Weeks 2, 4, 12, and 24
Population: ITT population; n=number of samples
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between MPA Levels and Risk of Gastrointestinal Toxicity | Free MPA (n=300) | 0.106 correlation coefficient |
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between MPA Levels and Risk of Gastrointestinal Toxicity | Total MPA (n=308) | 0.142 correlation coefficient |
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between MPA Levels and Risk of Gastrointestinal Toxicity | AUC MPA (n=152) | 0.187 correlation coefficient |
p-value: 0.0656ANOVA
p-value: 0.0131ANOVA
p-value: 0.0515ANOVA
Secondary
Spearman's Rank Correlation Coefficient Between MPA Levels and Risk of Hematologic Toxicity
The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used.
Time frame: BL and Weeks 2, 4, 12, and 24
Population: ITT population; n=number of samples
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between MPA Levels and Risk of Hematologic Toxicity | Free MPA (n=300) | -0.004 correlation coefficient |
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between MPA Levels and Risk of Hematologic Toxicity | Total MPA (n=308) | -0.037 correlation coefficient |
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between MPA Levels and Risk of Hematologic Toxicity | AUC MPA (n=152) | -0.038 correlation coefficient |
p-value: 0.9432ANOVA
p-value: 0.5177ANOVA
p-value: 0.6398ANOVA
Secondary
Spearman's Rank Correlation Coefficient Between MPA Levels and Risk of Infection
The Spearman's rank correlation coefficient was computed by ranking the data from 2 time points, 0 minutes and 120 minutes, and using the ranks in the Pearson product-moment correlation formula. In case of ties, the averaged ranks were used.
Time frame: BL and Weeks 2, 4, 12, and 24
Population: ITT population; n=number of samples
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between MPA Levels and Risk of Infection | Free MPA (n=300) | -0.020 correlation coefficient |
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between MPA Levels and Risk of Infection | Total MPA (n=308) | 0.063 correlation coefficient |
| MMF Monotherapy | Spearman's Rank Correlation Coefficient Between MPA Levels and Risk of Infection | AUC MPA (n=152) | 0.030 correlation coefficient |
p-value: 0.7332ANOVA
p-value: 0.2681ANOVA
p-value: 0.7087ANOVA
Secondary
Total Mycophenolate Acid (MPA) by Visit and Timepoint
Drug quantification of total MPA (micrograms per milliliter \[mcg/mL\]) in the plasma was measured at time (T) = 0 minutes (min), 40 mins, and 120 mins.
Time frame: Weeks 2, 4, 12, 24, and 28 (Safety Follow-Up Visit), and any unscheduled visits
Population: ITT population; n=number of samples analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MMF Monotherapy | Total Mycophenolate Acid (MPA) by Visit and Timepoint | T=0, Week 2 (n=41) | 1.75 mcg/mL | Standard Deviation 1.49 |
| MMF Monotherapy | Total Mycophenolate Acid (MPA) by Visit and Timepoint | T=0, Week 4 (n=42) | 1.87 mcg/mL | Standard Deviation 1.62 |
| MMF Monotherapy | Total Mycophenolate Acid (MPA) by Visit and Timepoint | T=0, Week 12 (n=35) | 1.79 mcg/mL | Standard Deviation 1.04 |
| MMF Monotherapy | Total Mycophenolate Acid (MPA) by Visit and Timepoint | T=0, Week 24 (n=35) | 1.90 mcg/mL | Standard Deviation 1.53 |
| MMF Monotherapy | Total Mycophenolate Acid (MPA) by Visit and Timepoint | T=0, safety follow-up (n=3) | 1.16 mcg/mL | Standard Deviation 0.22 |
| MMF Monotherapy | Total Mycophenolate Acid (MPA) by Visit and Timepoint | T=0, unscheduled visit (n=7) | 1.32 mcg/mL | Standard Deviation 0.67 |
| MMF Monotherapy | Total Mycophenolate Acid (MPA) by Visit and Timepoint | T=0, overall mean value (n=163) | 1.79 mcg/mL | Standard Deviation 1.4 |
| MMF Monotherapy | Total Mycophenolate Acid (MPA) by Visit and Timepoint | T=40, Week 2 (n=43) | 6.44 mcg/mL | Standard Deviation 4.37 |
| MMF Monotherapy | Total Mycophenolate Acid (MPA) by Visit and Timepoint | T=40, Week 4 (n=42) | 6.96 mcg/mL | Standard Deviation 3.92 |
| MMF Monotherapy | Total Mycophenolate Acid (MPA) by Visit and Timepoint | T=40, Week 12 (n=35) | 7.23 mcg/mL | Standard Deviation 4.27 |
| MMF Monotherapy | Total Mycophenolate Acid (MPA) by Visit and Timepoint | T=40, Week 24 (n=35) | 6.47 mcg/mL | Standard Deviation 3.35 |
| MMF Monotherapy | Total Mycophenolate Acid (MPA) by Visit and Timepoint | T=40, safety follow-up (n=3) | 5.71 mcg/mL | Standard Deviation 0.55 |
| MMF Monotherapy | Total Mycophenolate Acid (MPA) by Visit and Timepoint | T=40, unscheduled visit (n=7) | 4.06 mcg/mL | Standard Deviation 1.05 |
| MMF Monotherapy | Total Mycophenolate Acid (MPA) by Visit and Timepoint | T=40, overall mean value (n=165) | 6.63 mcg/mL | Standard Deviation 3.91 |
| MMF Monotherapy | Total Mycophenolate Acid (MPA) by Visit and Timepoint | T=120, Week 2 (n=41) | 8.86 mcg/mL | Standard Deviation 7.3 |
| MMF Monotherapy | Total Mycophenolate Acid (MPA) by Visit and Timepoint | T=120, Week 4 (n=42) | 8.95 mcg/mL | Standard Deviation 6.33 |
| MMF Monotherapy | Total Mycophenolate Acid (MPA) by Visit and Timepoint | T=120, Week 12 (n=35) | 8.57 mcg/mL | Standard Deviation 6.71 |
| MMF Monotherapy | Total Mycophenolate Acid (MPA) by Visit and Timepoint | T=120, safety follow-up (n=3) | 4.91 mcg/mL | Standard Deviation 2.09 |
| MMF Monotherapy | Total Mycophenolate Acid (MPA) by Visit and Timepoint | T=120, Week 24 (n=35) | 10.04 mcg/mL | Standard Deviation 6.91 |
| MMF Monotherapy | Total Mycophenolate Acid (MPA) by Visit and Timepoint | T=120, unscheduled visit (n=7) | 7.03 mcg/mL | Standard Deviation 5.31 |
| MMF Monotherapy | Total Mycophenolate Acid (MPA) by Visit and Timepoint | T=120, overall mean value (n=163) | 8.92 mcg/mL | Standard Deviation 6.68 |
Secondary
Tumor Necrosis Factor (TNF) Expression by Visit and Timepoint
TNF gene expression was measured by QRT-PCR based cytokine measurement of PBMCs at 2 timepoints per visit, 0 and 120 minutes and expressed as number of mRNA copies/cell.
Time frame: BL and Weeks 2, 4, 12, and 24, and safety follow-up (Week 28) and any unscheduled visits
Population: ITT population; n=number of samples analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MMF Monotherapy | Tumor Necrosis Factor (TNF) Expression by Visit and Timepoint | T=0, BL (n=44) | 4532.72 number of mRNA copies/cell | Standard Deviation 11598.93 |
| MMF Monotherapy | Tumor Necrosis Factor (TNF) Expression by Visit and Timepoint | T=0, Week 2 (n=41) | 29960.41 number of mRNA copies/cell | Standard Deviation 128979.24 |
| MMF Monotherapy | Tumor Necrosis Factor (TNF) Expression by Visit and Timepoint | T=0, Week 4 (n=42) | 54101.30 number of mRNA copies/cell | Standard Deviation 262581.32 |
| MMF Monotherapy | Tumor Necrosis Factor (TNF) Expression by Visit and Timepoint | T=0, Week 12 (n=34) | 1829.87 number of mRNA copies/cell | Standard Deviation 6411.17 |
| MMF Monotherapy | Tumor Necrosis Factor (TNF) Expression by Visit and Timepoint | T=0, Week 24 (n=34) | 10391.60 number of mRNA copies/cell | Standard Deviation 42574.52 |
| MMF Monotherapy | Tumor Necrosis Factor (TNF) Expression by Visit and Timepoint | T=0, safety follow-up (n=3) | 1254.29 number of mRNA copies/cell | Standard Deviation 1150.4 |
| MMF Monotherapy | Tumor Necrosis Factor (TNF) Expression by Visit and Timepoint | T=0, unscheduled visit (n=7) | 19148.94 number of mRNA copies/cell | Standard Deviation 49991.25 |
| MMF Monotherapy | Tumor Necrosis Factor (TNF) Expression by Visit and Timepoint | T=0, mean value (n=205) | 20748.32 number of mRNA copies/cell | Standard Deviation 133817.1 |
| MMF Monotherapy | Tumor Necrosis Factor (TNF) Expression by Visit and Timepoint | T=120, BL (n=0) | 0 number of mRNA copies/cell | Standard Deviation 0 |
| MMF Monotherapy | Tumor Necrosis Factor (TNF) Expression by Visit and Timepoint | T=120, Week 2 (n=43) | 1028.93 number of mRNA copies/cell | Standard Deviation 4210.43 |
| MMF Monotherapy | Tumor Necrosis Factor (TNF) Expression by Visit and Timepoint | T=120, Week 4 (n=42) | 21227.11 number of mRNA copies/cell | Standard Deviation 103517.73 |
| MMF Monotherapy | Tumor Necrosis Factor (TNF) Expression by Visit and Timepoint | T=120, Week 12 (n=35) | 12022.83 number of mRNA copies/cell | Standard Deviation 63647.48 |
| MMF Monotherapy | Tumor Necrosis Factor (TNF) Expression by Visit and Timepoint | T=120, Week 24 (n=34) | 9418.65 number of mRNA copies/cell | Standard Deviation 29084 |
| MMF Monotherapy | Tumor Necrosis Factor (TNF) Expression by Visit and Timepoint | T=120, safety follow-up (n=3) | 397887.30 number of mRNA copies/cell | Standard Deviation 688477.81 |
| MMF Monotherapy | Tumor Necrosis Factor (TNF) Expression by Visit and Timepoint | T=120, unscheduled visit (n=7) | 220.14 number of mRNA copies/cell | Standard Deviation 457.26 |
| MMF Monotherapy | Tumor Necrosis Factor (TNF) Expression by Visit and Timepoint | T=120, mean value (n=164) | 17512.31 number of mRNA copies/cell | Standard Deviation 110920.39 |