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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT01292226
First received: February 3, 2011
Last updated: February 23, 2015
Last verified: February 2015
  Purpose

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.


Condition Intervention Phase
Kidney Transplantation
Drug: mycophenolate mofetil
Drug: antibody induction
Drug: Cyclosporine
Drug: corticosteroid
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Relationships Between Pharmacokinetic and Pharmacodynamic Strategies for Assessment of the Risks for Acute Rejection and Side Effects of Mycophenolate Mofetil

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Percentage of Participants With Acute Rejection [ Time Frame: Day 1, Weeks 2, 4, 12, 24, and 28 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Day 1, Weeks 2, 4, 12, 24, and 28 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Day 1, Weeks 2, 4, 12, 24, and 28 ] [ Designated as safety issue: No ]
    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 Outcome Measures:
  • Percentage of Participants With Graft Loss [ Time Frame: Day 1, Weeks 2, 4, 12, 24, and 28 ] [ Designated as safety issue: No ]
    An allograft was presumed to be lost if a participant started dialysis and was not able to subsequently be removed from dialysis.

  • Percentage of Participants Surviving [ Time Frame: Day 1, Weeks 2, 4, 12, 24, and 28 ] [ Designated as safety issue: No ]
  • Total Mycophenolate Acid (MPA) by Visit and Timepoint [ Time Frame: Weeks 2, 4, 12, 24, and 28 (Safety Follow-Up Visit), and any unscheduled visits ] [ Designated as safety issue: No ]
    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.

  • Free MPA (mcg/mL) by Visit [ Time Frame: Weeks 2, 4, 12, 24, safety follow-up (Week 28), and any unscheduled visits ] [ Designated as safety issue: No ]
    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 [ 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) ] [ Designated as safety issue: No ]
    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 [ Time Frame: BL and Weeks 2, 4, 12, and 24, and safety follow-up (Week 28) and any unscheduled visits ] [ Designated as safety issue: No ]
    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 [ Time Frame: BL and Weeks 2, 4, 12, and 24, and safety follow-up (Week 28) and any unscheduled visits ] [ Designated as safety issue: No ]
    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 [ Time Frame: BL and Weeks 2, 4, 12, and 24, and safety follow-up (Week 28) and any unscheduled visits ] [ Designated as safety issue: No ]
    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 [ Time Frame: BL and Weeks 2, 4, 12, and 24, and safety follow-up (Week 28) and any unscheduled visits ] [ Designated as safety issue: No ]
    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 [ Time Frame: BL and Weeks 2, 4, 12, and 24, and safety follow-up (Week 28) and any unscheduled visits ] [ Designated as safety issue: No ]
    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 [ Time Frame: BL and Weeks 2, 4, 12, 24, and 28 (Safety Follow-Up) ] [ Designated as safety issue: Yes ]
    Infections were graded according to the World Health Organization (WHO) worst grade observed.

  • Percentage of Participants With Gastrointestinal Toxicities [ Time Frame: BL and Weeks 2, 4, 12, 24, and 28 (Safety Follow-up Visit) ] [ Designated as safety issue: Yes ]
    Gastrointestinal adverse events (AEs) according to WHO worst grade observed.

  • Percentage of Participants With Hematologic Toxicity [ Time Frame: BL and Weeks 2, 4, 12, 24, and 28 (Safety Follow-Up) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: BL and Weeks 2, 4, 12, and 24 ] [ Designated as safety issue: No ]
    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 [ Time Frame: BL and Weeks 2, 4, 12, and 24 ] [ Designated as safety issue: No ]
    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 Free Fraction [ Time Frame: BL and Weeks 2, 4, 12, and 24 ] [ Designated as safety issue: No ]
    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 [ Time Frame: BL and Weeks 2, 4, 12, and 24 ] [ Designated as safety issue: No ]
    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 [ Time Frame: BL and Weeks 2, 4, 12, and 24 ] [ Designated as safety issue: No ]
    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 [ Time Frame: BL and Weeks 2, 4, 12, and 24 ] [ Designated as safety issue: No ]
    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 [ Time Frame: BL and Weeks 2, 4, 12, and 24 ] [ Designated as safety issue: No ]
    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 [ Time Frame: BL and Weeks 2, 4, 12, and 24 ] [ Designated as safety issue: No ]
    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 [ Time Frame: BL and Weeks 2, 4, 12, and 24 ] [ Designated as safety issue: No ]
    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 [ Time Frame: BL and Weeks 2, 4, 12, and 24 ] [ Designated as safety issue: No ]
    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 [ Time Frame: BL and Weeks 2, 4, 12, and 24 ] [ Designated as safety issue: No ]
    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 [ Time Frame: BL and Weeks 2, 4, 12, and 24 ] [ Designated as safety issue: No ]
    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.


Enrollment: 45
Study Start Date: December 2006
Study Completion Date: September 2008
Primary Completion Date: September 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Mycophenolate Mofetil Monotherapy
Participants received an initial dose of mycophenolate mofetil (MMF), 1 gram (g), orally (PO), twice per day (BID), within 5 days of transplant for 24 weeks. Participants also received concurrent antibody induction, cyclosporine, and corticosteroids as needed according to center's practice.
Drug: mycophenolate mofetil
1 g PO BID for 24 weeks
Other Name: CellCept
Drug: antibody induction
According to manufacturer recommendation
Drug: Cyclosporine
According to manufacturer recommendation
Drug: corticosteroid
According to manufacturer recommendation

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01292226

Locations
Italy
Bari, Italy, 70124
Brescia, Italy, 25123
Coppito, Italy, 67100
Napoli, Italy, 80131
Roma, Italy, 00168
Torino, Italy, 10126
Verona, Italy, 37126
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Chair: Clinical Trials Hoffmann-La Roche
  More Information

No publications provided

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01292226     History of Changes
Other Study ID Numbers: ML19835
Study First Received: February 3, 2011
Results First Received: October 3, 2014
Last Updated: February 23, 2015
Health Authority: Italy: Ministry of Health

Additional relevant MeSH terms:
Cyclosporine
Cyclosporins
Mycophenolate mofetil
Mycophenolic Acid
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antineoplastic Agents
Antirheumatic Agents
Dermatologic Agents
Enzyme Inhibitors
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on April 27, 2015