Pharmacokinetics of LCP-Tacro™ Once Daily and Prograf® Twice A Day in Adult De Novo Liver 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 and liver. 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 liver 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 was a randomized, parallel-group, open-label, multicenter study in adult de novo liver transplant patients to demonstrate the pharmacokinetics and safety of once-daily treatment of LCP-Tacro tablets and twice-daily Prograf capsules in the first 2 weeks after live transplantation. The study also compared the efficacy and safety of LCP-Tacro and Prograf over an additional 50 weeks after liver transplantation. Eligible patients were randomized (1:1 ratio) within 72 hours after transplantation (graft reperfusion) to receive either: 1) LCP-Tacr tablets orally once daily (QD) in the morning, with an interval of 24 +/- 1 hours between dosed, starting at 0.07 to 0.11 mg/kg (the starting daily dose for African-American patients was 0.09 to 0.13 mg/kg), or 2) Prograf capsules in 2 equally divided morning and evening doses, starting at 0.10 to 0.15 mg. Subsequent doses of study medications were to be adjusted by the investigator according to local practice to maintain a target whole blood tacrolimus trough level of 5 to 20 ng/mL thought Day 14. Twenty-four-hour pharmacokinetic assessments were performed on Days 1, 7 and 14; additionally whole blood tacrolimus trough levels for statistical analysis were measured on Days 2, 3, 4, 7, 10, 12, 12, 42, 90, 120, 180, 270, and 360. Physicians could also perform tacrolimus trough levels at other times at their discretion. On Day 360, the patients were placed on maintenance immunosuppressive regimen determined by their treating physician. Following completion of the third and final pharmacokinetic assessment on Day 14, patients entered the maintenance phase (Days 15 to 360) of 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. Immunosuppressive therapy after the conclusion of the study was to be administered at the discretion of the patient's population.

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 Liver Transplant Patients

Conditions
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Liver Failure

Intervention / Treatment
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* Drug: LCP -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 liver transplant from a deceased donor with a Model for End-Stage Liver Disease (MELD) score at the time of transplantation of ≤ 30 who are able to give informed consent for participation Exclusion Criteria: Recipient of any transplanted organ other than a liver Recipients of a liver from a non-heart beating donor Recipients of a liver from an ABO incompatible donor 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 who fail a drugs of abuse screen in the pre-transplant evaluation 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 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, or hepatocellular carcinoma (HCC) that meet the Milan Criteria for liver transplantation 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 Randomization to one of two treatment groups will be done post transplantation provided that the patient fulfills the following additional criteria: Patient is able to receive their first dose of randomized study drug orally within 72 hours after the transplant surgery (graft reperfusion) Patient was NOT given intravenous tacrolimus prior to their first oral dose of study medication Recipient of a liver with a cold ischemia time of ≤ 10 hours

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>LCP - Tacro™ tablets, once daily (LifeCycle Pharma A/S, Hørsholm DK) | Drug: LCP -Tacro<br>* LCP-Tacro tablets will be administered orally once daily in the morning starting at 0.07 - 0.11 mg/kg. The starting dose for African-American patients will be 0.09 - 0.13 mg/kg. Subsequent doses of each study drug will be adjusted to maintain target whole blood tacrolimus trough levels of 5 - 20 ng/mL. Other Names:Tacrolimus modified-release LCP-Tacro™ tablets (0.5 mg, 1 mg, 2 mg, 5 mg)<br>* Other names: tacrolimus;|
| Active Comparator: Prograf (tacrolimus)<br>Prograf® capsules, twice daily (Astellas Pharma US, Deerfield IL) | Drug: Prograf<br>* Oral Prograf capsules will be administered starting at 0.10 - 0.15 mg/kg per day in two equally divided morning and evening doses. Subsequent doses of each study drug will be adjusted to maintain target whole blood tacrolimus trough levels of 5 - 20 ng/mL. Other name: tacrolimus Prograf® capsules (0.5 mg, 1 mg, 5 mg)<br>* Other names: tacrolimus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (Cmax and Cmin) of LCP-Tacro™ Compared to Prograf Early After Transplantations (Within the First 14 Days) in Adult de Novo Liver Transplant Recipients. | The pharmacokinetic parameters (Cmax and Cmin) were evaluated during the first 14 days after liver transplant (on days 1, 7 and 14). The results for Day 14 is listed below as the primary outcome parameter for this study. | 14 days | 
| Pharmacokinetics (AUC0-24) of LCP-Tacro™ Compared to Prograf Early After Transplantations (Within the First 14 Days) in Adult de Novo Liver Transplant Recipients. | The pharmacokinetic parameter (AUC, 0 to 24 hours post dose) was evaluated during the first 14 days after liver transplant (on days 1, 7 and 14). The results for Day 14 is listed below as the primary outcome parameter for this study. | 14 days | 
| Percentage of Patients in Each Treatment Group Achieving Sufficient Tacrolimus Whole Blood Trough Levels (5 to 20 ng/mL) During the First 14 Days Post-transplantation. | Percentage of patients with trough levels within the therapeutic range of 5 to 20 ng/mL was assessed during the initial 14 days (on days 1, 7 and 14) after liver transplant and compared between the two treatment groups. | 1 day | 
| Percentage of Patients in Each Treatment Group Achieving Sufficient Tacrolimus Whole Blood Trough Levels (5 to 20 ng/mL) During the First 14 Days Post-transplantation. | Percentage of patients with trough levels within the therapeutic range of 5 to 20 ng/mL was assessed during the initial 14 days (on days 1, 7 and 14) after liver transplant and compared between the two treatment groups. | 7 days | 
| Percentage of Patients in Each Treatment Group Achieving Sufficient Tacrolimus Whole Blood Trough Levels (5 to 20 ng/mL) During the First 14 Days Post-transplantation. | Percentage of patients with trough levels within the therapeutic range of 5 to 20 ng/mL was assessed during the initial 14 days (on days 1, 7 and 14) after liver transplant and compared between the two treatment groups. | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Died Within the 360 Days. | Number of patients who died was compared between the two groups during the study. | 360 days | 

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