Pharmacokinetics of LCP-Tacro(TM) Once Daily And Prograf® Twice A Day in Adult De Novo Kidney Transplant Patients

Study Overview
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Brief Summary
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The purpose of this study is to demonstrate the pharmacokinetics (PK, measuring the amount of medication in blood samples) and safety of a new medicine, LCP-Tacro™ tablets, and Prograf® capsules, a drug commonly taken by transplant recipients to prevent the body from rejecting a transplanted kidney. LCP-Tacro is a tablet containing the same active ingredient (tacrolimus) that is in Prograf capsules, but the tablet has been designed to release tacrolimus over an extended period so that it only has to be taken once daily. LCP-Tacro is an investigational drug. This study will evaluate the levels of tacrolimus in the blood in the first two weeks after a kidney transplant in patients randomly assigned (by chance, like flipping a coin) to take either LCP-Tacro™ tablets (tacrolimus) once daily or Prograf® capsules twice daily. In addition, patients will remain on study drug for 360 days in order to evaluate the relative safety of LCP-Tacro™ tablets compared to Prograf over a longer period of time.

Detailed Description
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This study was a randomized, parallel-group, open label, multicenter study in adult de novo kidney transplant patients to demonstrate the pharmacokinetics and safety of LCP-Tacro tablets and Prograf capsules in the first 2 weeks after kidney transplantation. In addition the study compared the efficacy and safety of LCP-Tacro and Prograf over an additional 50 weeks after kidney transplantation. Eligible patients were randomized (1:1 ratio) within 12 hours after transplantation (Day 0) to receive either: 1) LCP-Tacro tablets orally once daily (QD) in the morning, with an interval of 24+/- hours between doses, starting at 0.14 mg/kg (the starting daily dose for African-American patients was 0.17 mg/kg), or 2) Prograf capsules in 2 equally divided doses for African-American patients was (0.2 mg/kg total daily dose) as recommended in the U.S. Prescribing Information (Astellas Pharma US, April 2006). Day 1 was defined as the day on which the first morning dose of study medication was given which was to be within 48 hours of transplantation. Subsequent doses of study medication were adjusted to maintain target whole blood tacrolimus trough level of 7 to 20 ng/mL for the remainder of the pharmacokinetic phase of the study (Day1 through Day 14). Twenty-four-hour pharmacokinetic assessments were performed on Days 1, 7, and 14. Following completion of the third and final pharmacokinetic assessment on the morning of Day 14, patients entered the maintenance phase (Days 15 to 360) of the study and remained on their assigned study medication until Day 360. Visits for safety assessments and tacrolimus trough levels during the maintenance phase were on Days 42, 90, 120, 180, 270, and 360. On Day 360, the patients were placed on a maintenance immunosuppressive regimen determined by their treating physician.

Official Title
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A Phase 2, Open-Label, Multi-Center, Randomized Trial To Demonstrate The Pharmacokinetics Of LCP-Tacro™ Tablets Once Daily and Prograf® Capsules Twice Daily In Adult De Novo Kidney Transplant Patients

Conditions
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Kidney Failure, Renal Failure

Intervention / Treatment
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* Drug: Tacrolimus (Tacro™)
* Drug: Prograf


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult men and women at least 18 years of age who are recipients of a kidney transplant from a deceased donor or a live donor and who receive their first oral dose of randomized study drug within 48 hours of the transplant surgery (graft reperfusion) Exclusion Criteria: Recipient of any transplanted organ other than a kidney Recipients of a kidney from a non-heart beating donor Recipients of a kidney from an ABO incompatible donor Recipients of a kidney with a cold ischemia time of ≥ 36 hours Recipients of a bone marrow or stem cell transplant Patients with a white blood cell count ≤ 2.8 x 109/L unless the absolute neutrophil count (ANC) is > 1.0 x 109/L Patients with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) enzyme levels > 3 times the upper limit of normal during the 30 days prior to the transplant procedure Patients who fail a drugs of abuse screen Patients unable to swallow study medication Patients incapable of understanding the purposes and risks of the study, who cannot give written informed consent, or who are unwilling to comply with the study protocol Pregnant or nursing women (women of childbearing potential must have a negative serum pregnancy test within seven days prior to receiving study medication) Patients with reproductive potential who are unwilling/unable to use a double barrier method of contraception throughout the duration of the study Patients who were treated with any other investigational agent in the 30 days prior to enrollment Patients who are hepatitis C virus (HCV) negative who have received a HCV positive (HCV RNA by polymerase chain reaction (PCR) or HCV antibody) donor kidney Patients seropositive for human immunodeficiency virus (HIV) Patients with a current malignancy or a history of malignancy (within the past 5 years), except basal or non-metastatic squamous cell carcinoma of the skin that has been treated successfully Patients with uncontrolled concomitant infection, a systemic infection requiring treatment, or any other unstable medical condition that could interfere with the study objectives Patients with severe diarrhea, vomiting, active peptic ulcer or gastrointestinal disorder that may affect the absorption of tacrolimus Patients with a known hypersensitivity to tacrolimus Patients with any form of current substance abuse, psychiatric disorder or a condition that, in the opinion of the Investigator, may invalidate communication with the investigator

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LCP-Tacro<br>The initial dose starting at 0.14 mg/kg (the starting daily dose for African-American patients was 0.17 mg/kg), will be administered orally in the morning (before noon) within 12 hours after transplantation. Subsequent doses adjusted to maintain a target whole blood tacrolimus trough level of 7 - 20 ng/mL for the remainder of the pharmacokinetic (PK) phase of the study (through Study Day 14). Post PK patient enter the maintenance phase of the study and remain on assigned study drug until Study Day 360. Dose of study drug was adjusted to maintain tacrolimus trough levels between 5 - 20 ng/mL from Day 15 until Day 90 and then between 5 - 15 ng/mL for the remainder of the study according to local standard of care. | Drug: Tacrolimus (Tacro™)<br>* The initial dose at 0.14 mg/kg (daily dose for African-American is 0.17 mg/kg), oral in the morning (before noon) within 12 hours after transplantation. Subsequent doses adjusted to maintain a target tacrolimus trough level of 7 - 20 ng/mL for (PK) phase of the study (through Study Day 14). Post PK maintenance phase of the study and remain on assigned study drug until Study Day 360. Dose of study drug was adjusted to maintain tacrolimus trough levels between 5 - 20 ng/mL from Day 15 until Day 90 and then between 5 - 15 ng/mL for the remainder of the study according to local standard of care. Other Names: Tacrolimus modified-release<br>* Other names: LCP -Tacro;|
| Active Comparator: Prograf (tacrolimus)<br>Starting total daily dose of 0.10 mg/kg administered in two equally divided doses, morning and evening, per product labeling. Subsequent doses adjusted to maintain a target whole blood tacrolimus trough level of 7 - 20 ng/mL for the remainder of the pharmacokinetic (PK) phase of the study (through Study Day 14). Post PK patient enter the maintenance phase of the study and remain on assigned study drug until Study Day 360. Dose of study drug was adjusted to maintain tacrolimus trough levels between 5 - 20 ng/mL from Day 15 until Day 90 and then between 5 - 15 ng/mL for the remainder of the study according to local standard of care. Other name: tacrolimus | Drug: Prograf<br>* Prograf® capsules, twice daily: Starting total daily dose of 0.10 mg/kg administered in two equally divided doses, morning and evening, per product labeling. Subsequent doses adjusted to maintain a target whole blood tacrolimus trough level of 7 - 20 ng/mL for the remainder of the pharmacokinetic (PK) phase of the study (through Study Day 14). Post PK patient enter the maintenance phase of the study and remain on assigned study drug until Study Day 360. Dose of study drug was adjusted to maintain tacrolimus trough levels between 5 - 20 ng/mL from Day 15 until Day 90 and then between 5 - 15 ng/mL for the remainder of the study according to local standard of care. Other name: tacrolimus<br>* Other names: tacrolimus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of LCP-Tacro™ Tablets in the First 14 Days After Transplantation in Adult de Novo Kidney Recipients. | Comparison of the proportion of patients achieving sufficient tacrolimus whole blood trough levels (7 to 20 ng/mL) during the first 14 days post-transplantation | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparative Pharmacokinetics Between LCP-Tacro and Prograf Within 14 Days After Kidney Transplantation. | To compare the pharmacokinetics (AUC, Cmax, C24/Cmin) on Days 1, 7 and 14 of LCP-Tacro with the pharmacokinetics of Prograf in adult de novo kidney transplant patients. | 14 days | 
| Evaluation of Safety and Efficacy of LCP-Tacro Compared to Prograf in Adult de Novo Kidney Transplant Patients. | To evaluate the efficacy and safety of LCP-Tacro compared to Prograf in the first 12 months after kidney transplantation. Efficacy was assessed by monitoring biopsy-proven acute rejection (BPAR) according to the Banff criteria, graft failure (defined by a patient starting dialysis for at least 30 days, nephrectomy, retransplantation, or death with a functioning graft), patient survival, and renal function based on serum creatinine and glomerular filtration rate (GFR), based on serum creatinine, serum urea nitrogen, and serum albumin. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunosuppression, Kidney, Transplantation, Tacrolimus, Prograf