Renal Failure
Conditions
Keywords
Tacrolimus, Pharmacokinetics, Kidney Transplantation
Brief summary
A three sequence, open-label, multi-center, prospective, study in stable kidney transplant patients to assess and compare the pharmacokinetics (Cmax, C24, and AUC), and safety of LCP-Tacro (tacrolimus) tablets versus Prograf (tacrolimus) capsules.
Detailed description
A three sequence, open-label, multi-center, prospective, study in stable kidney transplant patients to assess and compare the pharmacokinetics (Cmax, C24, and AUC), and safety of LCP-Tacro (tacrolimus) tablets versus Prograf (tacrolimus) capsules. Stable kidney transplant patients who fulfill all I/E criteria will be enrolled and kept on Prograf for 7 days. Following a 24-hour PK study on Day 7 to determine pharmacokinetics for Prograf, all patients will be converted to once daily LCP-Tacro for 7 days with no dose changes allowed. On Day 14 and Day 21 a 24-hour LCP-Tacro PK study will be performed. On Day 22 patients will be converted back to their original twice daily dose of Prograf for a safety follow-up period of 30 days ending with a safety assessment on day 53.
Interventions
Prograf will be administrated twice a day, per product labeling, with an interval of 12 ± 1 hours between the morning and evening doses. Patients will continue on the same dose on Day0 through Day 7 to maintain target trough levels of 7-12 ng/mL. On the morning of Day 8, following the final blood draw for the PK assessment, patient will be converted to LCP-Tacro using the conversion Ratio 0.66-0.8. LCP-Tacro tablets will be administered orally once daily in the morning, with an interval of 24 ± 1 hours between doses. Other Names: Tacrolimus modified-release LCP-Tacro tablets were provided in 3 strengths: 1 mg, 2 mg, and 5 mg oral tablets.
DRUGPrograf
Prograf will be administrated twice a day, per product labeling, with an interval of 12 ± 1 hours between the morning and evening doses. Patients will continue on the same dose on Day0 through Day 7 to maintain target trough levels of 7-12 ng/mL. On the morning of Day 8, following the final blood draw for the PK assessment, patient will be converted to LCP-Tacro using the conversion Ratio 0.66-0.8. LCP-Tacro tablets will be administered orally once daily in the morning, with an interval of 24 ± 1 hours between doses. Other Names: Tacrolimus modified-release LCP-Tacro tablets were provided in 3 strengths: 1 mg, 2 mg, and 5 mg oral tablets.
Sponsors
CTI Clinical Trial and Consulting Services
Veloxis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Men and women 18-65 years of age who are recipients of a renal transplant at least 6 months prior to enrollment * Patients on oral Prograf therapy as part of their maintenance immunosuppression therapy, with stable doses and trough levels of tacrolimus of 7-12 ng/mL for at least two weeks prior to enrollment. * Patients maintained on concurrent immunosuppression with mycophenolate mofetil (MMF, CellCept) or mycophenolic acid delayed-release tablets (Myfortic), with stable doses for at least two weeks prior to enrollment * Patients with serum creatinine \< 2.0mg/dL prior to enrollment * Able to swallow study medication * Patients capable of understanding the purposes and risks of the study, who can give written informed consent and who are willing to participate in and comply with the study * Women of childbearing potential must have a negative serum pregnancy test within seven days prior to receiving study medication * Patients who successfully pass a drug screen
Exclusion criteria
* Recipients of any transplanted organ other than a kidney * White blood cell count \< 2.8 x 10\^9 /L * Patients who are receiving a total dose of Prograf for 24 hours \< 3mg * Patients unable or unwilling to provide informed consent * Pregnant or nursing women * Patients with reproductive potential who are unwilling/unable to use a double barrier method of contraception * Administration of other investigational agent in the three months prior to enrollment * Patient receiving any drug interfering with tacrolimus metabolism * Patients who have taken sirolimus within the past three months prior to screening * Patient with an episode of acute cellular requiring antibody therapy within the 6 months prior to enrollment * Patient treated for acute cellular rejection within the 30 days prior to enrollment * Patient who is HCV negative and has received an HCV positive (HCV RNA by PCR or HCV antibody) donor kidney * Patient has 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 * Patient has uncontrolled concomitant infection, a systemic infection requiring treatment, or any other unstable medical condition that could interfere with the study objectives * Patient has severe diarrhea, vomiting, active peptic ulcer or gastrointestinal disorder that may affect the absorption of tacrolimus * Patient will require therapy with any immunosuppressive agent other than those prescribed in the study * Patient has a known hypersensitivity to corticosteroids, mycophenolate mofetil, mycophenolic acid or tacrolimus * Patient has any form of current substance abuse, psychiatric disorder or a condition that, in the opinion of the Investigator, may invalidate communication with the Investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of Steady State Tacrolimus Trough Levels (C24). | 7 days | Patients had a baseline trough level (C24) measured at day 7 before conversion to LCP-Tacro. |
| Evaluation of Steady State Tacrolimus Exposure (AUC 0-24). | 7 days | Patients had a baseline AUC measured (0 to 24 hours) at day 7 before conversion to LCP-Tacro. |
| Evaluation of Steady State Tacrolimus Exposure Trough Levels (C24). | 21 days | Patients were converted from Prograf to LCP-Tacro on day 7. On day 21, a trough level (C24) was measured. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tacrolimus Pharmacokinetics (Cmax and Cavg) Was Measured at Day 7. | 7 days | Cmax and Cavg was measured at baseline day 7 (Cmin was measured as part of the primary outcome). |
| Tacrolimus Pharmacokinetics (Tmax) Was Measured at Day 7. | 7 days | Tmax was measured at baseline day 7 (Cmin was measured as part of the primary outcome). |
| Tacrolimus Pharmacokinetics (Cmax and Cavg) Was Measured at Day 21. | 21 days | Cmax and Cavg was measured at day 21 (Cmin was measured as part of the primary outcome). |
| Safety Evaluation | 52 days | A combination of deaths, graft failure and biopsy proven acute rejections (BPAR) was used to evaluate the safety. |
| Tacrolimus Pharmacokinetics (Fluctuation and Swing) Was Measured at Day 7. | 7 days | Degree og fluctuation and degree of swing was measured as baseline at day 7 (Cmin was measured as part of the primary outcome). |
| Tacrolimus Pharmacokinetics (Tmax) Was Measured at Day 21. | 21 days | Tmax was measured at day 21 (Cmin was measured as part of the primary outcome). |
| Tacrolimus Pharmacokinetics (Fluctuation and Swing) Was Measured at Day 21. | 21 days | Degree og fluctuation and degree of swing was measured at day 21 (Cmin was measured as part of the primary outcome). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LCP-Tacro LCP-Tacro 1 mg, 2 mg and 5 mg tablets administered orally QD, dosing per conversion algorithm to maintain tacrolimus trough concentrations between 7 to 12 ng/mL. | 60 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Lack of Efficacy | 1 |
| Overall Study | Not dosed | 9 |
Baseline characteristics
| Characteristic | LCP-Tacro |
|---|---|
| Age, Continuous | 45.6 years STANDARD_DEVIATION 12.08 |
| Region of Enrollment United States | 60 participants |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 35 / 51 | 19 / 59 |
| serious Total, serious adverse events | 2 / 51 | 0 / 59 |
Outcome results
Primary
Evaluation of Steady State Tacrolimus Exposure (AUC 0-24).
Patients had a baseline AUC measured (0 to 24 hours) at day 7 before conversion to LCP-Tacro.
Time frame: 7 days
Population: 48 completed treatment with LCP-Tacro but one patient was excluded from the PP analysis due to inappropriate conversion rate.~The arithmetic mean and standard deviation is given.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LCP-Tacro | Evaluation of Steady State Tacrolimus Exposure (AUC 0-24). | 218.82 ng*hr/mL | Standard Deviation 55.99 |
Primary
Evaluation of Steady State Tacrolimus Exposure (AUC 0-24).
Patients were converted from Prograf to LCP-Tacro on day 7. On day 21, AUC was measured (0 to 24 hours).
Time frame: 21 days
Population: 48 completed treatment with LCP-Tacro but one patient was excluded from the PP analysis due to inappropriate conversion rate. Another patient discontinued before the Day 21 visit.~The arithmetic mean and standard deviation is given.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LCP-Tacro | Evaluation of Steady State Tacrolimus Exposure (AUC 0-24). | 218.03 ng*hr/mL | Standard Deviation 68.23 |
Primary
Evaluation of Steady State Tacrolimus Exposure Trough Levels (C24).
Patients were converted from Prograf to LCP-Tacro on day 7. On day 21, a trough level (C24) was measured.
Time frame: 21 days
Population: 48 completed treatment with LCP-Tacro but one patient was excluded from the PP analysis due to inappropriate conversion rate. Another patient discontinued before the Day 21 visit.~The arithmetic mean and standard deviation is given.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LCP-Tacro | Evaluation of Steady State Tacrolimus Exposure Trough Levels (C24). | 6.94 ng/mL | Standard Deviation 2.2 |
Primary
Evaluation of Steady State Tacrolimus Trough Levels (C24).
Patients had a baseline trough level (C24) measured at day 7 before conversion to LCP-Tacro.
Time frame: 7 days
Population: 48 completed treatment with LCP-Tacro but one patient was excluded from the PP analysis due to inappropriate conversion rate.~The arithmetic mean and standard deviation is given.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| LCP-Tacro | Evaluation of Steady State Tacrolimus Trough Levels (C24). | 7.00 ng/mL | Standard Deviation 1.54 |
Secondary
Safety Evaluation
A combination of deaths, graft failure and biopsy proven acute rejections (BPAR) was used to evaluate the safety.
Time frame: 52 days
Population: All enrolled patients are included in the safety population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LCP-Tacro | Safety Evaluation | Death | 0 participants |
| LCP-Tacro | Safety Evaluation | Graft failure | 0 participants |
| LCP-Tacro | Safety Evaluation | BPAR | 0 participants |
Secondary
Tacrolimus Pharmacokinetics (Cmax and Cavg) Was Measured at Day 21.
Cmax and Cavg was measured at day 21 (Cmin was measured as part of the primary outcome).
Time frame: 21 days
Population: 48 completed treatment with LCP-Tacro but one patient was excluded from the PP analysis due to inappropriate conversion rate. Another patient discontinued before the Day 21 visit.~The arithmetic mean and standard deviation is given.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LCP-Tacro | Tacrolimus Pharmacokinetics (Cmax and Cavg) Was Measured at Day 21. | Cmax | 13.94 ng/mL | Standard Deviation 5.84 |
| LCP-Tacro | Tacrolimus Pharmacokinetics (Cmax and Cavg) Was Measured at Day 21. | Cavg | 9.08 ng/mL | Standard Deviation 2.84 |
Secondary
Tacrolimus Pharmacokinetics (Cmax and Cavg) Was Measured at Day 7.
Cmax and Cavg was measured at baseline day 7 (Cmin was measured as part of the primary outcome).
Time frame: 7 days
Population: 48 completed treatment with LCP-Tacro but one patient was excluded from the PP analysis due to inappropriate conversion rate.~The arithmetic mean and standard deviation is given.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LCP-Tacro | Tacrolimus Pharmacokinetics (Cmax and Cavg) Was Measured at Day 7. | Cmax | 19.14 ng/mL | Standard Deviation 8.15 |
| LCP-Tacro | Tacrolimus Pharmacokinetics (Cmax and Cavg) Was Measured at Day 7. | Cavg | 9.12 ng/mL | Standard Deviation 2.33 |
Secondary
Tacrolimus Pharmacokinetics (Fluctuation and Swing) Was Measured at Day 21.
Degree og fluctuation and degree of swing was measured at day 21 (Cmin was measured as part of the primary outcome).
Time frame: 21 days
Population: 48 completed treatment with LCP-Tacro but one patient was excluded from the PP analysis due to inappropriate conversion rate. Another patient discontinued before the Day 21 visit.~Arithmetic mean and standard deviation is given below.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LCP-Tacro | Tacrolimus Pharmacokinetics (Fluctuation and Swing) Was Measured at Day 21. | Fluctuation | 77.04 percentage | Standard Deviation 50.59 |
| LCP-Tacro | Tacrolimus Pharmacokinetics (Fluctuation and Swing) Was Measured at Day 21. | Swing | 110.07 percentage | Standard Deviation 89.23 |
Secondary
Tacrolimus Pharmacokinetics (Fluctuation and Swing) Was Measured at Day 7.
Degree og fluctuation and degree of swing was measured as baseline at day 7 (Cmin was measured as part of the primary outcome).
Time frame: 7 days
Population: 48 completed treatment with LCP-Tacro but one patient was excluded from the PP analysis due to inappropriate conversion rate.~Arithmetic mean and standard deviation is given below.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LCP-Tacro | Tacrolimus Pharmacokinetics (Fluctuation and Swing) Was Measured at Day 7. | Fluctuation | 127.41 percentage | Standard Deviation 57.28 |
| LCP-Tacro | Tacrolimus Pharmacokinetics (Fluctuation and Swing) Was Measured at Day 7. | Swing | 174.55 percentage | Standard Deviation 93.72 |
Secondary
Tacrolimus Pharmacokinetics (Tmax) Was Measured at Day 21.
Tmax was measured at day 21 (Cmin was measured as part of the primary outcome).
Time frame: 21 days
Population: 48 completed treatment with LCP-Tacro but one patient was excluded from the PP analysis due to inappropriate conversion rate. Another patient discontinued before the Day 21 visit.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| LCP-Tacro | Tacrolimus Pharmacokinetics (Tmax) Was Measured at Day 21. | 6.00 hour |
Secondary
Tacrolimus Pharmacokinetics (Tmax) Was Measured at Day 7.
Tmax was measured at baseline day 7 (Cmin was measured as part of the primary outcome).
Time frame: 7 days
Population: 48 completed treatment with LCP-Tacro but one patient was excluded from the PP analysis due to inappropriate conversion rate. Another patient discontinued before the Day 21 visit.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| LCP-Tacro | Tacrolimus Pharmacokinetics (Tmax) Was Measured at Day 7. | 1.82 hour |