A Study to Assess the Pharmacokinetics of a Modified-release Tacrolimus Based Immunosuppression Regimen in Stable Kidney Transplant Patients

A Phase 2, Open-Label, Multi-center Study to Assess the Pharmacokinetics, Safety and Tolerability of Tacrolimus in Stable Kidney Transplant Patients Converted From a Prograf® Based Immunosuppression Regimen to a Modified Release (MR) Tacrolimus Based Immunosuppression Regimen

A study to assess the pharmacokinetics, safety and effectiveness of tacrolimus in stable kidney transplant patients converted from a Prograf® based immunosuppression regimen to a modified release tacrolimus based immunosuppression regimen.

Study Overview

• Status: Completed
• Conditions: Kidney Transplantation
• Intervention / Treatment: Drug: tacrolimus; Drug: Tacrolimus Modified Release (MR)

Detailed Description

This is a Phase II open-label, multi-center conversion study in stable, adult kidney transplant recipients to assess the pharmacokinetics, safety and effectiveness of tacrolimus in stable kidney transplant patients converted from a Prograf® based immunosuppression regimen to a modified release tacrolimus based immunosuppression regimen.

• Study Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
  • Ontario
    • Toronto, Ontario, Canada, M5C 2T2
• United States
  • California
    • San Diego, California, United States
  • Florida
    • Miami, Florida, United States, 33136
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
  • Ohio
    • Cincinnati, Ohio, United States, 45267
  • Oregon
    • Portland, Oregon, United States, 97239
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
    • Milwaukee, Wisconsin, United States, 53226

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient is currently receiving Prograf ® based immunosuppressive therapy for kidney transplantation.
• Patient has stable whole blood trough level concentrations of Prograf® and is clinically stable

Exclusion Criteria:

• Patient has previously received an organ transplant other than a kidney
• Patient is currently receiving sirolimus immunosuppression therapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Tacrolimus Modified Release; Participants were enrolled into the study on their stable twice-daily (bid) dose of tacrolimus on Day 1 and continued to receive a stable bid dose of tacrolimus through Day 7. Participants then converted to Tacrolimus Modified Release (MR), administered once daily at an equivalent dose to the patient's previous stable total daily dose of tacrolimus. Participants who completed the 4-week pharmacokinetic treatment period with tacrolimus MR could continue receiving tacrolimus MR as part of the extended treatment period of the study. Dose adjustments were allowed in order to maintain tacrolimus trough concentrations within the target range of 5 to 15 ng/mL and for clinical reasons.

Drug: tacrolimus; Oral; Other Names: FK506; Prograf®; Drug: Tacrolimus Modified Release (MR); Oral; Other Names: Advagraf; FK506E; Astagraf XL; MR4; FKMR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) for Tacrolimus	The area under the concentration-time curve was calculated from whole blood tacrolimus concentrations for both tacrolimus and tacrolimus MR at steady state using the trapezoidal rule.	For tacrolimus, Days 1 and 7 at 0 (pre-dose), 0.5, 1, 2, 3, 6, 8, 12 (pre-dose), 13, 14, 15, 18, 20, and 24 hours. For tacrolimus MR, Days 14 and 21 pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 15, 18, 20, and 24 hours post-dose.
Maximum Observed Concentration (Cmax) of Tacrolimus	The maximum concentration was calculated from whole blood tacrolimus concentrations for both tacrolimus and tacrolimus MR at steady state, without interpolation.	For tacrolimus, Days 1 and 7 at 0 (pre-dose), 0.5, 1, 2, 3, 6, 8, 12 (pre-dose), 13, 14, 15, 18, 20, and 24 hours. For tacrolimus MR, Days 14 and 21 pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 15, 18, 20, and 24 hours post-dose.
Minimum Concentration of Tacrolimus (Cmin)	The trough (minimum) concentration of tacrolimus determined from the tacrolimus whole blood concentration value at the 24-hour time point post- dose, prior to receiving the next dose.	Days 1 and 7 (tacrolimus) and Days 14 and 21 (tacrolimus MR), 24 hours post-dose.
Time to Maximum Observed Concentration of Tacrolimus (Tmax)	The time to reach the maximum concentration of tacrolimus was calculated from whole blood tacrolimus concentrations for both tacrolimus and tacrolimus MR at steady state, without interpolation.	For tacrolimus, Days 1 and 7 at 0 (pre-dose), 0.5, 1, 2, 3, 6, 8, 12 (pre-dose), 13, 14, 15, 18, 20, and 24 hours. For tacrolimus MR, Days 14 and 21 pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 15, 18, 20, and 24 hours post-dose.
Patient Survival	Patient Survival defined as any participant who did not die by the time of analysis.	From enrollment until the end of study (up to 60 months).
Graft Survival	Graft survival was defined as any participant who did not meet the definition of graft loss, where graft loss was defined as graft failure (re-transplant or permanent return to dialysis (for more than 30 days)) or participants death.	From enrollment until the end of study (up to 60 months).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Biopsy-confirmed Acute Rejection	Biopsy-confirmed acute rejection (BCAR) is defined as an episode of acute allograft rejection that was confirmed by biopsy results and was Banff grade ≥ IA. Biopsies were graded by the pathologist at the clinical site according to the 1997 Banff criteria: Borderline: No intimal arteritis present but foci of mild tubulitis; Grade I: Significant interstitial infiltration and foci of moderate to severe tubulitis; Grade II: Mild to severe intimal arteritis; Grade III: Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic infiltrate in vessel.	From enrollment until the end of study (up to 60 months).
Change From Baseline in Serum Creatinine	Renal function was assessed using serum creatinine levels over the course of the study.	Baseline (the last day of tacrolimus on Day 7), Day 35 (end of the pharmacokinetic phase) and end of treatment (EOT; the last observed value during treatment, maximum time on study was 60 months).
Change From Baseline in Creatinine Clearance	Renal function was assessed using creatinine clearance levels calculated using the Cockcroft-Gault formula, over the course of the study.	Baseline (the last day of tacrolimus on Day 7), Day 35 (end of the pharmacokinetic phase) and end of treatment (EOT; the last observed value during treatment, maximum time on study was 60 months).
Time to Event for Patient Non Survival	For participants who died on study, the median number of days from enrollment to death due to any cause.	From enrollment until the end of study (up to 60 months).
Time to Event for Graft Non Survival	For participants with graft loss, the median number of days from enrollment to graft loss. Graft loss was defined as graft failure (re-transplant or permanent return to dialysis (for more than 30 days)) or participant death.	From enrollment until the end of study (up to 60 months).
Time to First Biopsy-confirmed Acute Rejection	For participants with a biopsy-confirmed acute rejection, the median number of days from enrollment to the date of biopsy confirmation. Biopsy-confirmed acute rejection (BCAR) is defined as an episode of acute allograft rejection that was confirmed by biopsy results and was Banff grade ≥ IA. Biopsies were graded by the pathologist at the clinical site according to the 1997 Banff criteria: Borderline: No intimal arteritis present but foci of mild tubulitis; Grade I: Significant interstitial infiltration and foci of moderate to severe tubulitis; Grade II: Mild to severe intimal arteritis; Grade III: Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic infiltrate in vessel.	From enrollment until the end of study (up to 60 months).
Grade of Biopsy-confirmed Acute Rejection Episodes	Biopsy-confirmed acute rejection (BCAR) is defined as an episode of acute allograft rejection that was confirmed by biopsy results and was Banff grade ≥ IA. Biopsies were graded by the pathologist at the clinical site according to the 1997 Banff criteria: Borderline: No intimal arteritis present but foci of mild tubulitis; Grade I: Significant interstitial infiltration and foci of moderate to severe tubulitis; Grade II: Mild to severe intimal arteritis; Grade III: Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic infiltrate in vessel. For participants with more than one biopsy-confirmed acute rejection episode, the worst case grade is reported.	From enrollment until the end of study (up to 60 months).
Number of Participants Receiving Anti-lymphocyte Antibody Therapy for Acute Rejection	Steroid-resistant rejection episodes were treated with anti-lymphocyte antibodies. If a participant had a histologically proven Banff Grade II or III rejection, they could be initiated on anti-lymphocyte antibody treatment per institutional practice. Biopsies were graded by the pathologist at the clinical site according to the 1997 Banff criteria: Borderline: No intimal arteritis present but foci of mild tubulitis; Grade I: Significant interstitial infiltration and foci of moderate to severe tubulitis; Grade II: Mild to severe intimal arteritis; Grade III: Transmural arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells with accompanying lymphocytic infiltrate in vessel.	From enrollment until the end of study (up to 60 months).
Number of Participants With Multiple Rejection Episodes	This analysis includes rejection episodes that were either confirmed by biopsy by the clinical site pathologist or were clinically treated.	From enrollment until the end of study (up to 60 months).
Number of Participants With Clinically Treated Acute Rejection Episodes	A clinically treated acute rejection episode was any biopsy-confirmed or suspected rejection episode that was treated with immunosuppressive therapy.	From enrollment until the end of study (up to 60 months).
Number of Participants With Chronic Rejection	Due to the low number of participants with biopsy-confirmed acute rejection episodes, chronic rejection was not analyzed.	From enrollment until the end of study (up to 60 months).
Number of Participants With Treatment Failure	Treatment failure was defined as discontinuation of study drug for any reason. Due to discontinuation of the study by the sponsor, treatment failure was not analyzed.	From enrollment until the end of study (up to 60 months).
Primary Reason for Graft Loss	The primary reason for graft loss was recorded by the Investigator. Graft loss was defined as graft failure (re-transplant or permanent return to dialysis) or death. GBM = glomerular basement membrane.	From enrollment until the end of study (up to 60 months).
Number of Participants Returning to Permanent Dialysis	Permanent dialysis defined as dialysis for longer than 30 days.	From enrollment until the end of study (up to 60 months).
Safety as Assessed by Adverse Events, Laboratory Parameters and Vital Signs	An adverse event was defined as any reaction, side effect or other untoward medical occurrence, regardless of the relationship to study drug which occurred during the conduct of a clinical study. Clinically significant adverse changes in clinical status, routine laboratory studies or physical examinations were considered adverse events. A serious adverse event was any adverse event occurring at any dose that resulted in any of the following outcomes: Death; Life-threatening adverse event; Inpatient hospitalization or prolongation of existing hospitalization; Persistent or significant disability or incapacity; Congenital abnormality or birth defect; Important medical event.	From the first dose of tacrolimus MR formulation through the day of last dose plus 10 days (approximately 60 months).

Collaborators and Investigators

• Sponsor: Astellas Pharma Inc
• Investigators: Study Director: Central Contact, Astellas Pharma US, Inc.

Publications and helpful links

General Publications

• Alloway R, Steinberg S, Khalil K, Gourishankar S, Miller J, Norman D, Hariharan S, Pirsch J, Matas A, Zaltzman J, Wisemandle K, Fitzsimmons W, First MR. Two years postconversion from a prograf-based regimen to a once-daily tacrolimus extended-release formulation in stable kidney transplant recipients. Transplantation. 2007 Jun 27;83(12):1648-51. doi: 10.1097/01.tp.0000264056.20105.b4.
• Alloway R, Steinberg S, Khalil K, Gourishankar S, Miller J, Norman D, Hariharan S, Pirsch J, Matas A, Zaltzman J, Wisemandle K, Fitzsimmons W, First MR. Conversion of stable kidney transplant recipients from a twice daily Prograf-based regimen to a once daily modified release tacrolimus-based regimen. Transplant Proc. 2005 Mar;37(2):867-70. doi: 10.1016/j.transproceed.2004.12.222.

Study record dates

Study Major Dates

• Study Start: August 1, 2002
• Primary Completion (Actual): October 1, 2008
• Study Completion (Actual): October 1, 2008

Study Registration Dates

• First Submitted: January 25, 2006
• First Submitted That Met QC Criteria: January 25, 2006
• First Posted (Estimate): January 27, 2006

Study Record Updates

• Last Update Posted (Estimate): September 26, 2013
• Last Update Submitted That Met QC Criteria: July 25, 2013
• Last Verified: July 1, 2013

More Information

Terms related to this study

• Keywords: Immunosuppression; Pharmacokinetics; Adult; Therapy; Drugs, Investigational
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: 02-0-131