Renal Failure
Conditions
Brief summary
Open label, prospective, single-center, randomized, two sequence, three period crossover study to compare the steady state pharmacokinetics of LCP-Tacro tables to generic tacrolimus capsules administered twice daily in stable African-American renal transplant patients.
Detailed description
This is open label, prospective, single-center, randomized, two sequence, three period crossover study to compare the steady state pharmacokinetics of once daily dosing of LCP-Tacro tablets to tacrolimus capsules administered twice daily in stable African American kidney transplant patients. Approximately 72 male and female African American renal transplant patients on table immunosuppression regimens will be randomly assigned in a 1:1 ratio to one of two sequences: Sequence 1: (n=36) 18 patients requiring less than 0.15 mg/kg/day and 18 patients requiring equal to or greater than 0.15 mg/kg/day. Patients will continue on generic tacrolimus capsules on days 1-7 (24 hours PK profile on day 7) then patients are switched to LCP-Tacro tablets (at 15% lower dose of twice daily generic tacrolimus) on day 8. Sequence 2: (n=36) 18 patients requiring less than 0.15 mg/kg/day and 18 patients requiring equal to or greater than 0.15 mg/kg/day. Patients will receive LCP-Tacro tablets (at 15% lower dose than generic tacrolimus twice daily formulation) on days 1-7 (24 hour PK profile on day 7) patients are switched back to twice daily generic tacrolimus treatment beginning on day 8.
Interventions
DRUGLCP-Tacro
once-daily extended release tablet
DRUGTacrolimus -IR
twice daily capsules
Sponsors
Veloxis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Age ≥18-80 old, male or female * African Americans * Willing to give written informed consent and to comply with study visits and restrictions, including being able to speak, write and understand English * Pt who have received a primary or secondary transplant * Pt least 6 (six) mth post-transplant and on a stable dose of tacrolimus * BMI ≥19 * Pt who are sero-positive for Hepatitis B or C positive may also be enrolled * Pt maintained on concurrent immunosuppression with stable doses during screening * Pt on a proton PPI remain on the same PPI formulation and dose during the PK portion of the study. * During PK phase Only: Pt taking any medication that could interfere with tacrolimus blood levels, including prescription and over-the-counter medications, herbal or food supplements (including grapefruit, and pomegranate products), or medications must continue the same dose and are willing to continue the same dose/routine * During PK phase Only: the patient is not scheduled to begin any new medication that could interfere with tacrolimus blood levels, including prescription and over-the-counter medications, herbal or food
Exclusion criteria
* Evidence of acute rejection episode within the past three months * Pt not Africa-American * Recipients of organ transplants other than kidney * Known to be HIV positive at transplant * Pt with recurrent focal segmental glomerulosclerosis (FSGS) * Pt with any severe medical condition (including infection) requiring acute or chronic treatment * Pt with a positive DSA * Pt with a positive BK virus results * GFR \< 25 ml/min measured by MDRD4 as SOC within last 30 days * Patients with AST, ALT, total bilirubin \> 2.5 x ULN or evidence of severe liver disease * Pt with WBC \< to 2000/mm3 or ANC \< to 1500 mm3 with PLT \< 75,000/mm3 or HGB \< 8 g/dl * Pt with mental or physical conditions or known non-adherence * Presence of intractable immunosuppressant complications of side effects resulting in dose adjustment of tacrolimus * Exposed to investigational therapy within 30 days prior to enrollment * No anticipated changes in the immunosuppressive regimen, other than those specified by the study protocol * Pt with severe diabetic gastroparesis or other severe GI disturbances * Pt who have underwent gastric banding or gastric bypass at any time pre or post-transplant * Pregnant or nursing (lactating) women, or planning to become pregnant * Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant who are unwilling to use a defined SOC of method
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of AUC(0-24) for Envarsus XR and IR-Tac | Day 7 | Tacrolimus whole blood concentrations obtained from the central lab was used for PK analysis. Actual sampling time was used to calculate AUC(0-24). Arithmetic mean and standard deviation is given below. Nominal time points used were: Pre-dose (C0) and then 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 13, 14, 16, 18 and 24 hours. |
| Evaluation of C(Max) for Envarsus XR and IR-Tac | Day 7 | Tacrolimus whole blood concentrations obtained from the central lab was used for PK analysis. Actual sampling time was used to calculate C(max). Arithmetic mean and standard deviation is given below. Nominal time points used were: Pre-dose (C0) and then 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 13, 14, 16, 18 and 24 hours. |
| Evaluation of C(Min) for Envarsus XR and IR-Tac | Day 7 | Tacrolimus whole blood concentrations obtained from the central lab was used for PK analysis. Actual sampling time was used to calculate AUC(0-24). Arithmetic mean and standard deviation is given below. Nominal time points used were: Pre-dose (C0) and then 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 13, 14, 16, 18 and 24 hours. |
Countries
United States
Participant flow
Recruitment details
25 November 2013 (first patient enrolled) to 09-Mar-2015 (last patient completed initial pharmacokinetics \[PK\] portion of the study, the 'PK Cross-over' period), approximately 16 months enrolled from 3 US medical centers:University of Pennsylvania;University of Illinois at Chicago;Washington School of Medicine
Participants by arm
| Arm | Count |
|---|---|
| Sequence I Sequence I IR-Tac→Envarsus XR (N = 27) | 27 |
| Sequence II Sequence II Envarsus XR→IR-Tac (N = 23) | 23 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Extendion Portion (up to Month 6) | no longer wished to participate in study | 4 | 3 |
| Extendion Portion (up to Month 6) | Physician Decision | 1 | 0 |
| PK Portion Day 7 | non-compliance | 1 | 0 |
| PK Portion Day 7 | Withdrawal by Subject | 3 | 0 |
Baseline characteristics
| Characteristic | Sequence I | Sequence II | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 3 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 26 Participants | 20 Participants | 46 Participants |
| Region of Enrollment United States | 27 participants | 23 participants | 50 participants |
| Sex: Female, Male Female | 12 Participants | 9 Participants | 21 Participants |
| Sex: Female, Male Male | 15 Participants | 14 Participants | 29 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 23 / 50 | 22 / 50 |
| serious Total, serious adverse events | 3 / 50 | 4 / 50 |
Outcome results
Primary
Evaluation of AUC(0-24) for Envarsus XR and IR-Tac
Tacrolimus whole blood concentrations obtained from the central lab was used for PK analysis. Actual sampling time was used to calculate AUC(0-24). Arithmetic mean and standard deviation is given below. Nominal time points used were: Pre-dose (C0) and then 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 13, 14, 16, 18 and 24 hours.
Time frame: Day 21
Population: For this outcome measure the PK population N=46 was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Envarsus XR | Evaluation of AUC(0-24) for Envarsus XR and IR-Tac | 289.3 ng*hr/mL | Standard Deviation 111.79 |
| Tacrolimus - IR | Evaluation of AUC(0-24) for Envarsus XR and IR-Tac | 230.3 ng*hr/mL | Standard Deviation 53.83 |
Primary
Evaluation of AUC(0-24) for Envarsus XR and IR-Tac
Tacrolimus whole blood concentrations obtained from the central lab was used for PK analysis. Actual sampling time was used to calculate AUC(0-24). Arithmetic mean and standard deviation is given below. Nominal time points used were: Pre-dose (C0) and then 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 13, 14, 16, 18 and 24 hours.
Time frame: Day 7
Population: For this outcome measure the PK population N=46 was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Envarsus XR | Evaluation of AUC(0-24) for Envarsus XR and IR-Tac | 251.9 ng*hr/mL | Standard Deviation 77.78 |
| Tacrolimus - IR | Evaluation of AUC(0-24) for Envarsus XR and IR-Tac | 247.9 ng*hr/mL | Standard Deviation 102.33 |
Primary
Evaluation of AUC(0-24) for Envarsus XR and IR-Tac
Tacrolimus whole blood concentrations obtained from the central lab was used for PK analysis. Actual sampling time was used to calculate AUC(0-24). Arithmetic mean and standard deviation is given below. Nominal time points used were: Pre-dose (C0) and then 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 13, 14, 16, 18 and 24 hours.
Time frame: Day 14
Population: For this outcome measure the PK population N=46 was used
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Envarsus XR | Evaluation of AUC(0-24) for Envarsus XR and IR-Tac | 293.3 ng*hr/mL | Standard Deviation 124.4 |
| Tacrolimus - IR | Evaluation of AUC(0-24) for Envarsus XR and IR-Tac | 225.7 ng*hr/mL | Standard Deviation 56.27 |
Primary
Evaluation of C(Max) for Envarsus XR and IR-Tac
Tacrolimus whole blood concentrations obtained from the central lab was used for PK analysis. Actual sampling time was used to calculate C(max). Arithmetic mean and standard deviation is given below. Nominal time points used were: Pre-dose (C0) and then 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 13, 14, 16, 18 and 24 hours.
Time frame: Day 14
Population: For this outcome measuure the Protocol PK population of N = 46 was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Envarsus XR | Evaluation of C(Max) for Envarsus XR and IR-Tac | 20.83 ng/mL | Standard Deviation 9.265 |
| Tacrolimus - IR | Evaluation of C(Max) for Envarsus XR and IR-Tac | 26.31 ng/mL | Standard Deviation 13.296 |
Primary
Evaluation of C(Max) for Envarsus XR and IR-Tac
Tacrolimus whole blood concentrations obtained from the central lab was used for PK analysis. Actual sampling time was used to calculate C(max). Arithmetic mean and standard deviation is given below. Nominal time points used were: Pre-dose (C0) and then 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 13, 14, 16, 18 and 24 hours.
Time frame: Day 21
Population: For this outcome measuure the Protocol PK population of N = 46 was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Envarsus XR | Evaluation of C(Max) for Envarsus XR and IR-Tac | 19.71 ng/mL | Standard Deviation 8.387 |
| Tacrolimus - IR | Evaluation of C(Max) for Envarsus XR and IR-Tac | 26.31 ng/mL | Standard Deviation 7.871 |
Primary
Evaluation of C(Max) for Envarsus XR and IR-Tac
Tacrolimus whole blood concentrations obtained from the central lab was used for PK analysis. Actual sampling time was used to calculate C(max). Arithmetic mean and standard deviation is given below. Nominal time points used were: Pre-dose (C0) and then 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 13, 14, 16, 18 and 24 hours.
Time frame: Day 7
Population: For this outcome measuure the Protocol PK population of N = 46 was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Envarsus XR | Evaluation of C(Max) for Envarsus XR and IR-Tac | 16.53 ng/mL | Standard Deviation 5.464 |
| Tacrolimus - IR | Evaluation of C(Max) for Envarsus XR and IR-Tac | 26.84 ng/mL | Standard Deviation 13.296 |
Primary
Evaluation of C(Min) for Envarsus XR and IR-Tac
Tacrolimus whole blood concentrations obtained from the central lab was used for PK analysis. Actual sampling time was used to calculate AUC(0-24). Arithmetic mean and standard deviation is given below. Nominal time points used were: Pre-dose (C0) and then 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 13, 14, 16, 18 and 24 hours.
Time frame: Day 7
Population: For this outcome measure the Protocol PK population N= 46 was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Envarsus XR | Evaluation of C(Min) for Envarsus XR and IR-Tac | 7.51 ng/mL | Standard Deviation 2.487 |
| Tacrolimus - IR | Evaluation of C(Min) for Envarsus XR and IR-Tac | 7.06 ng/mL | Standard Deviation 2.843 |
Primary
Evaluation of C(Min) for Envarsus XR and IR-Tac
Tacrolimus whole blood concentrations obtained from the central lab was used for PK analysis. Actual sampling time was used to calculate AUC(0-24). Arithmetic mean and standard deviation is given below. Nominal time points used were: Pre-dose (C0) and then 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 13, 14, 16, 18 and 24 hours.
Time frame: Day 21
Population: For this outcome measure the Protocol PK population N= 46 was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Envarsus XR | Evaluation of C(Min) for Envarsus XR and IR-Tac | 8.01 ng/mL | Standard Deviation 3.281 |
| Tacrolimus - IR | Evaluation of C(Min) for Envarsus XR and IR-Tac | 6.62 ng/mL | Standard Deviation 1.692 |
Primary
Evaluation of C(Min) for Envarsus XR and IR-Tac
Tacrolimus whole blood concentrations obtained from the central lab was used for PK analysis. Actual sampling time was used to calculate AUC(0-24). Arithmetic mean and standard deviation is given below. Nominal time points used were: Pre-dose (C0) and then 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 13, 14, 16, 18 and 24 hours
Time frame: Day 14
Population: For this outcome measuure the Protocol PK population N= 46 was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Envarsus XR | Evaluation of C(Min) for Envarsus XR and IR-Tac | 8.34 ng/mL | Standard Deviation 3.769 |
| Tacrolimus - IR | Evaluation of C(Min) for Envarsus XR and IR-Tac | 6.46 ng/mL | Standard Deviation 1.692 |