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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
45
1 g PO BID for 24 weeks
According to manufacturer recommendation
According to manufacturer recommendation
Unnamed facility
Bari, Italy
Unnamed facility
Brescia, Italy
Unnamed facility
Coppito, Italy
Unnamed facility
Napoli, Italy
Unnamed facility
Roma, Italy
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
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
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
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
Percentage of Participants Surviving
Time frame: Day 1, Weeks 2, 4, 12, 24, and 28
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According to manufacturer recommendation
Unnamed facility
Torino, Italy
Unnamed facility
Verona, Italy
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
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
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)
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
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
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
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
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
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)
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)
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)
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
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
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
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
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
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
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
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
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
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
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
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