Renal Failure
Conditions
Keywords
Tacrolimus, Acute Rejection, Kidney
Brief summary
This study will evaluate the efficacy and safety of LCP-Tacro (tacrolimus) Tablets administered once-a-day compared to Prograf (tacrolimus) Capsules twice-a-day as immunosuppression for the prevention of organ rejection in newly transplanted adult kidney transplant recipients. Patients will be treated for a 12 month study period followed by a 12 month, blinded extension treatment period To show that LCP-Tacro Tablets are clinically similar to Prograf Capsules in the prevention of acute rejection.
Detailed description
This is a two-armed parallel group, prospective, randomized, double-blind, double-dummy,multicenter Phase 3 clinical study to establish the efficacy and safety of LCP-Tacro Tablets (tacrolimus, LifeCycle Pharma A/S, Hørsholm, Denmark) once daily for the prevention of allograft rejection in de novo adult male and female recipients of a primary or secondary kidney transplant evaluated by a combined efficacy endpoint comprised of acute rejection, graft loss and patient loss. The trial is designed to determine if the test drug, LCP-Tacro, is not inferior to an unacceptable extent to the reference compound, Prograf. Recipients of a kidney transplant who sign an informed consent form and fulfill all other inclusion and exclusion criteria will be randomly assigned to once-daily therapy with LCP-Tacro Tablets or to twice-daily therapy with Prograf Capsules (tacrolimus, Astellas Pharma US, Inc., Deerfield, IL), each concomitantly administered with mycophenolate mofetil (MMF) and corticosteroids. All patients will also receive interleukin-2 (IL-2) receptor antagonist (e.g.,Simulect®, basiliximab; Novartis Pharmaceuticals, East Hanover, NJ). Following screening,transplantation, and randomization, study visits will be conducted over a 12-month treatment period; with additional visits during a 12 month extension period on treatment and a follow-up safety assessment by visit or telephone interview 30 days after withdrawal from study drug.
Interventions
Administered per current product labeling
DRUGLCP-Tacro
Tacrolimus, once-per-day The initial dose of 0.17 mg/kg will be administered orally in the morning (before noon) within 24 hours following transplantation. Subsequent doses will be adjusted according to whole blood tacrolimus trough levels.
Sponsors
Veloxis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. informed consent 2. 18 and 70 years, inclusive 3. receiving primary or secondary renal allograft from a deceased donor or non-human leukocyte antigen (HLA) identical living donor 4. no known contraindications to the administration of IL-2 receptor antagonist induction therapy, MMF, corticosteroids or tacrolimus 5. negative pregnancy test 6. Negative cross match test, and compatible (A, B, AB or O) blood type 7. Able to swallow tablets and capsules
Exclusion criteria
1. Recipients of any non-renal transplant (solid organ or bone marrow) ever 2. Panel reactive antibody (PRA) \>30% 3. Patients with any condition that may affect study drug absorption (e.g. gastrectomy or clinically significant diabetic gastroenteropathy) 4. Body mass index (BMI) 18 kg/m2 5. History of alcohol abuse 6. History of recreational drug abuse 7. Screening 12-lead electrocardiogram (ECG) demonstrating clinically relevant abnormalities 8. WOCBP who are either pregnant, lactating, planning to become pregnant 9. Patients with an oral temperature (prior to study drug dosing) of 38.0 ºC (100.4 ºF) or higher 10. Patients with clinically significant active infections 11. Patients with a known hereditary immunodeficiency 12. Patients with malignancies or with a history of malignancies (within the last 5 years) 13. Patients who are receiving or expect to receive sirolimus, everolimus, azathioprine,or cyclophosphamide within 3 months prior to enrollment 14. Patients with evidence of clinically significant disease (e.g., cardiac, gastrointestinal or hepatic disorders) 15. Patients with reversible cardiac ischemia (history of untreated reversible ischemia on stress test) 16. Patients with clinically symptomatic congestive heart failure or documented ejection fraction of less than 45% 17. Patients with significant chronic obstructive pulmonary disease, pulmonary restrictive disease or significant pulmonary hypertension 18. Treatment with an investigational drug, device or regimen within 1 year preceding the first dose of study drug 19. Patients who are unwilling to refrain from consumption of grapefruit or grapefruit containing juices 20. Patients receiving concomitant drugs that may affect concentrations of tacrolimus in whole blood, as listed in Appendix 2 21. Laboratory variables that are abnormal (outside laboratory reference range) and clinically relevant, as judged by the Investigator 22. Patients with positive results of any of the following serological tests: human immunodeficiency virus (HIV)-1 antibody, hepatitis B virus (HBV) surface antigen (HBsAg), anti-hepatitis B core antibody (HBcAb), and anti-hepatitis C virus (HCV)antibody (HCV Ab). 23. Patients who experienced graft loss within 1 year of transplant, due to acute rejection or due to BK nephropathy 24. Patients having experienced focal segmental glomerulosclerosis (FSGS) 25. Donor with positive serological test result for HIV-1, HBV or HCV 26. Donor with history of malignant disease (current or historical) 27. Centers for Disease Control and Prevention high-risk donor 28. Patients with mental dysfunction or inability to cooperate with the study 29. Cold ischemia time \>30 hours 29\. Non-heart-beating donor
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Primary Efficacy Endpoint for the Study is the Proportion of Treatment Failures Within 12 Months After Randomization to Study Drug. | 360 days | Treatment failure is a composite endpoint; a patient is considered a treatment failure if the patient experienced any of the following events during this period: death, graft failure, BPAR (Banff grade ≥1A) or lost to follow-up. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| For the 24-month Analysis, the Endpoint Includes Additional Treatment Failures That Occurred During the 12-month Treatment Extension Period, up to Day 734 After the Randomization Date. | 734 days | Treatment failure is a composite endpoint; a patient is considered a treatment failure if the patient experienced any of the following events during this period (day 1 to day 734): death, graft failure, BPAR (Banff grade ≥1A) or lost to follow-up. |
Countries
Argentina, Australia, Brazil, France, Germany, Italy, Mexico, New Zealand, Poland, Serbia, Singapore, South Korea, Spain, Sweden, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LCP-Tacro The initial dose of 0.17 mg/kg will be administered orally in the morning (before noon) within 24 hours following transplantation. Subsequent doses will be adjusted according to whole blood tacrolimus trough levels.
LCP-Tacro: Tacrolimus, once-per-day The initial dose of 0.17 mg/kg will be administered orally in the morning (before noon) within 24 hours following transplantation. Subsequent doses will be adjusted according to whole blood tacrolimus trough levels. | 268 |
| Prograf (Tacrolimus) Starting total daily dose of 0.10 mg/kg administered in two equally divided doses, morning and evening, per product labeling. Doses will be adjusted according to whole blood tacrolimus trough levels. In the initial post-transplant period, plasma trough levels will be measured at 24 and 48 hours. Study drugs will be adjusted to maintain the whole blood pre-dose (trough) concentration of tacrolimus in the target range of 6 - 11 ng/mL for the first 30 days, then 4 - 11 ng/mL for the remainder of the study.
Prograf (tacrolimus): Administered per current product labeling | 275 |
| Total | 543 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Death | 11 | 13 |
| Overall Study | Lost to Follow-up | 0 | 3 |
| Overall Study | Withdrawal by Subject | 3 | 3 |
Baseline characteristics
| Characteristic | Prograf (Tacrolimus) | LCP-Tacro | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 28 Participants | 16 Participants | 44 Participants |
| Age, Categorical Between 18 and 65 years | 247 Participants | 252 Participants | 499 Participants |
| Age, Continuous | 46.9 years STANDARD_DEVIATION 14.26 | 44.8 years STANDARD_DEVIATION 13.29 | 45.8 years STANDARD_DEVIATION 13.82 |
| Body Mass Index | 26.68 kg/m^2 STANDARD_DEVIATION 4.948 | 25.72 kg/m^2 STANDARD_DEVIATION 4.648 | 26.21 kg/m^2 STANDARD_DEVIATION 4.822 |
| Diabetes at the time of transplant Patients with diabetes at transplant | 56 participants | 50 participants | 106 participants |
| Diabetes at the time of transplant Patients without diabetes at transplant | 219 participants | 218 participants | 437 participants |
| Donor Type Deceased | 145 participants | 133 participants | 278 participants |
| Donor Type Living | 129 participants | 135 participants | 264 participants |
| Donor Type Missing | 1 participants | 0 participants | 1 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 79 Participants | 74 Participants | 153 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 196 Participants | 194 Participants | 390 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 10 Participants | 10 Participants | 20 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants | 10 Participants | 25 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 34 Participants | 44 Participants | 78 Participants |
| Race (NIH/OMB) White | 214 Participants | 203 Participants | 417 Participants |
| Region of Enrollment Argentina | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Australia | 11 participants | 11 participants | 22 participants |
| Region of Enrollment Brazil | 29 participants | 29 participants | 58 participants |
| Region of Enrollment France | 38 participants | 35 participants | 73 participants |
| Region of Enrollment Germany | 35 participants | 32 participants | 67 participants |
| Region of Enrollment Italy | 6 participants | 6 participants | 12 participants |
| Region of Enrollment Mexico | 29 participants | 27 participants | 56 participants |
| Region of Enrollment New Zealand | 3 participants | 2 participants | 5 participants |
| Region of Enrollment Poland | 26 participants | 27 participants | 53 participants |
| Region of Enrollment Serbia | 5 participants | 6 participants | 11 participants |
| Region of Enrollment Singapore | 1 participants | 1 participants | 2 participants |
| Region of Enrollment Spain | 21 participants | 24 participants | 45 participants |
| Region of Enrollment United States | 70 participants | 67 participants | 137 participants |
| Sex: Female, Male Female | 94 Participants | 94 Participants | 188 Participants |
| Sex: Female, Male Male | 181 Participants | 174 Participants | 355 Participants |
| Time from transplant to first dose | 34.38 hours STANDARD_DEVIATION 9.735 | 34.15 hours STANDARD_DEVIATION 8.878 | 34.27 hours STANDARD_DEVIATION 9.312 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 263 / 268 | 269 / 275 |
| serious Total, serious adverse events | 166 / 268 | 185 / 275 |
Outcome results
Primary
The Primary Efficacy Endpoint for the Study is the Proportion of Treatment Failures Within 12 Months After Randomization to Study Drug.
Treatment failure is a composite endpoint; a patient is considered a treatment failure if the patient experienced any of the following events during this period: death, graft failure, BPAR (Banff grade ≥1A) or lost to follow-up.
Time frame: 360 days
Population: All 543 randomized patients were included in the analysis population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LCP-Tacro | The Primary Efficacy Endpoint for the Study is the Proportion of Treatment Failures Within 12 Months After Randomization to Study Drug. | Death | 8 participants |
| LCP-Tacro | The Primary Efficacy Endpoint for the Study is the Proportion of Treatment Failures Within 12 Months After Randomization to Study Drug. | Graft Failure | 9 participants |
| LCP-Tacro | The Primary Efficacy Endpoint for the Study is the Proportion of Treatment Failures Within 12 Months After Randomization to Study Drug. | Biobsy Proven Acute Rejection | 35 participants |
| LCP-Tacro | The Primary Efficacy Endpoint for the Study is the Proportion of Treatment Failures Within 12 Months After Randomization to Study Drug. | Lost to follow up | 4 participants |
| Prograf (Tacrolimus) | The Primary Efficacy Endpoint for the Study is the Proportion of Treatment Failures Within 12 Months After Randomization to Study Drug. | Lost to follow up | 5 participants |
| Prograf (Tacrolimus) | The Primary Efficacy Endpoint for the Study is the Proportion of Treatment Failures Within 12 Months After Randomization to Study Drug. | Death | 8 participants |
| Prograf (Tacrolimus) | The Primary Efficacy Endpoint for the Study is the Proportion of Treatment Failures Within 12 Months After Randomization to Study Drug. | Biobsy Proven Acute Rejection | 37 participants |
| Prograf (Tacrolimus) | The Primary Efficacy Endpoint for the Study is the Proportion of Treatment Failures Within 12 Months After Randomization to Study Drug. | Graft Failure | 11 participants |
Comparison: No overall p value was calculated, only individual p values for each endpoint category. One statistical analysis table is reported for each individual p value.p-value: >0.999Fisher Exact
Comparison: No overall p value was calculated, only individual p values for each endpoint category. One statistical analysis table is reported for each individual p value.p-value: 0.821Fisher Exact
Comparison: No overall p value was calculated, only individual p values for each endpoint category. One statistical analysis table is reported for each individual p value.p-value: 0.9Fisher Exact
Comparison: No overall p value was calculated, only individual p values for each endpoint category. One statistical analysis table is reported for each individual p value.p-value: >0.999Fisher Exact
Secondary
For the 24-month Analysis, the Endpoint Includes Additional Treatment Failures That Occurred During the 12-month Treatment Extension Period, up to Day 734 After the Randomization Date.
Treatment failure is a composite endpoint; a patient is considered a treatment failure if the patient experienced any of the following events during this period (day 1 to day 734): death, graft failure, BPAR (Banff grade ≥1A) or lost to follow-up.
Time frame: 734 days
Population: All 543 randomized patients were included in the analysis population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LCP-Tacro | For the 24-month Analysis, the Endpoint Includes Additional Treatment Failures That Occurred During the 12-month Treatment Extension Period, up to Day 734 After the Randomization Date. | Death | 11 participants |
| LCP-Tacro | For the 24-month Analysis, the Endpoint Includes Additional Treatment Failures That Occurred During the 12-month Treatment Extension Period, up to Day 734 After the Randomization Date. | Graft Failure | 11 participants |
| LCP-Tacro | For the 24-month Analysis, the Endpoint Includes Additional Treatment Failures That Occurred During the 12-month Treatment Extension Period, up to Day 734 After the Randomization Date. | Biobsy Proven Acute Rejection | 46 participants |
| LCP-Tacro | For the 24-month Analysis, the Endpoint Includes Additional Treatment Failures That Occurred During the 12-month Treatment Extension Period, up to Day 734 After the Randomization Date. | Lost to follow up | 4 participants |
| Prograf (Tacrolimus) | For the 24-month Analysis, the Endpoint Includes Additional Treatment Failures That Occurred During the 12-month Treatment Extension Period, up to Day 734 After the Randomization Date. | Lost to follow up | 8 participants |
| Prograf (Tacrolimus) | For the 24-month Analysis, the Endpoint Includes Additional Treatment Failures That Occurred During the 12-month Treatment Extension Period, up to Day 734 After the Randomization Date. | Death | 13 participants |
| Prograf (Tacrolimus) | For the 24-month Analysis, the Endpoint Includes Additional Treatment Failures That Occurred During the 12-month Treatment Extension Period, up to Day 734 After the Randomization Date. | Biobsy Proven Acute Rejection | 50 participants |
| Prograf (Tacrolimus) | For the 24-month Analysis, the Endpoint Includes Additional Treatment Failures That Occurred During the 12-month Treatment Extension Period, up to Day 734 After the Randomization Date. | Graft Failure | 15 participants |
Comparison: No overall p value was calculated, only individual p values for each endpoint category. One statistical analysis table is reported for each individual p value.p-value: 0.835Fisher Exact
Comparison: No overall p value was calculated, only individual p values for each endpoint category. One statistical analysis table is reported for each individual p value.p-value: 0.548Fisher Exact
Comparison: No overall p value was calculated, only individual p values for each endpoint category. One statistical analysis table is reported for each individual p value.p-value: 0.822Fisher Exact
Comparison: No overall p value was calculated, only individual p values for each endpoint category. One statistical analysis table is reported for each individual p value.p-value: 0.383Fisher Exact