A Study of the Correlation Between Pharmacokinetic and Pharmacodynamic Parameters of CellCept (Mycophenolate Mofetil).

Kidney Transplantation Clinical Trial

Official title:

Relationships Between Pharmacokinetic and Pharmacodynamic Strategies for Assessment of the Risks for Acute Rejection and Side Effects of Mycophenolate Mofetil

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01292226
• Other study ID #: ML19835
• Status: Completed
• Phase: Phase 2
• First received: February 3, 2011
• Last updated: February 23, 2015
• Start date: December 2006
• Est. completion date: September 2008

Study information

• Verified date: February 2015
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: Ministry of Health
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 45
• Est. completion date: September 2008
• Est. primary completion date: September 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Kidney Transplantation

Intervention

Drug:
• mycophenolate mofetil
1 g PO BID for 24 weeks
• antibody induction
According to manufacturer recommendation
• Cyclosporine
According to manufacturer recommendation
• corticosteroid
According to manufacturer recommendation

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	Day 1, Weeks 2, 4, 12, 24, and 28	No
Primary	Time to Rejection	The mean time, in days, from the date of enrollment to date of biopsy confirming acute rejection.	Day 1, Weeks 2, 4, 12, 24, and 28	No
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.	Day 1, Weeks 2, 4, 12, 24, and 28	No
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.	Day 1, Weeks 2, 4, 12, 24, and 28	No
Secondary	Percentage of Participants Surviving		Day 1, Weeks 2, 4, 12, 24, and 28	No
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.	Weeks 2, 4, 12, 24, and 28 (Safety Follow-Up Visit), and any unscheduled visits	No
Secondary	Free MPA (mcg/mL) by Visit	Drug quantification of free MPA in the plasma was measured at T = 0, 40, and 120 mins.	Weeks 2, 4, 12, 24, safety follow-up (Week 28), and any unscheduled visits	No
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).	Predose and 40 minutes and 2 hours postdose at Weeks 2, 4, 12, and 24, and at the Safety follow-up (Week 28)	No
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).	BL and Weeks 2, 4, 12, and 24, and safety follow-up (Week 28) and any unscheduled visits	No
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).	BL and Weeks 2, 4, 12, and 24, and safety follow-up (Week 28) and any unscheduled visits	No
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.	BL and Weeks 2, 4, 12, and 24, and safety follow-up (Week 28) and any unscheduled visits	No
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.	BL and Weeks 2, 4, 12, and 24, and safety follow-up (Week 28) and any unscheduled visits	No
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.	BL and Weeks 2, 4, 12, and 24, and safety follow-up (Week 28) and any unscheduled visits	No
Secondary	Percentage of Participants With Infection	Infections were graded according to the World Health Organization (WHO) worst grade observed.	BL and Weeks 2, 4, 12, 24, and 28 (Safety Follow-Up)	Yes
Secondary	Percentage of Participants With Gastrointestinal Toxicities	Gastrointestinal adverse events (AEs) according to WHO worst grade observed.	BL and Weeks 2, 4, 12, 24, and 28 (Safety Follow-up Visit)	Yes
Secondary	Percentage of Participants With Hematologic Toxicity	Hematological toxicities graded according to WHO worst grade observed (Grade 1=mild, Grade 2=moderate).	BL and Weeks 2, 4, 12, 24, and 28 (Safety Follow-Up)	Yes
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.	BL and Weeks 2, 4, 12, and 24	No
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.	BL and Weeks 2, 4, 12, and 24	No
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.	BL and Weeks 2, 4, 12, and 24	No
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.	BL and Weeks 2, 4, 12, and 24	No
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.	BL and Weeks 2, 4, 12, and 24	No
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.	BL and Weeks 2, 4, 12, and 24	No
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.	BL and Weeks 2, 4, 12, and 24	No
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.	BL and Weeks 2, 4, 12, and 24	No
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.	BL and Weeks 2, 4, 12, and 24	No
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.	BL and Weeks 2, 4, 12, and 24	No
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.	BL and Weeks 2, 4, 12, and 24	No
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.	BL and Weeks 2, 4, 12, and 24	No