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

Kidney Transplantation Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00282568
• Other study ID #: 02-0-131
• Status: Completed
• Phase: Phase 2
• First received: January 25, 2006
• Last updated: July 25, 2013
• Start date: August 2002
• Est. completion date: October 2008

Study information

• Verified date: July 2013
• Source: Astellas Pharma Inc
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationCanada: Health Canada
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 70
• Est. completion date: October 2008
• Est. primary completion date: October 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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 Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Kidney Transplantation

Intervention

Drug:
• Tacrolimus Modified Release (MR)
Oral
• tacrolimus
Oral

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Astellas Pharma Inc

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (2)

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	No
Primary	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.	No
Primary	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.	No
Primary	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.	No
Primary	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).	No
Primary	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).	No
Secondary	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).	No
Secondary	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).	No
Secondary	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).	No
Secondary	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).	No
Secondary	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).	No
Secondary	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).	No
Secondary	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).	No
Secondary	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).	No
Secondary	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).	No
Secondary	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).	No
Secondary	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).	No
Secondary	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).	No
Secondary	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).	No
Secondary	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).	No
Secondary	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).	No