| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Prevention of Acute Allograft Rejection in De Novo Adult Kidney Transplant Recipients |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 13.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10050436 |
| E.1.2 | Term | Prophylaxis against renal transplant rejection |
| E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the efficacy and safety of LCP-Tacro (tacrolimus) Tablets administered once daily compared to Prograf (tacrolimus) Capsules twice daily as immunosuppression for the prevention of acute allograft rejection in de novo adult kidney transplant recipients treated for a 12 month treatment period followed by a 12 month, blinded extension period.
To show that LCP-Tacro Tablets are not clinically inferior to Prograf Capsules in the
prevention of acute allograft rejection in de novo adult kidney transplant recipients. |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed informed consent.
2. Between the ages of 18 and 70 years, inclusive.
3. Patients must be receiving primary or secondary renal allograft from a deceased donor or non- human leukocyte antigen (HLA) identical living donor.
4. Patients must have no known contraindications to the administration of IL-2 receptor antagonist induction therapy, MMF, corticosteroids or tacrolimus.
5. Women of childbearing potential (WOCBP) must have a negative pregnancy test (serum or urine pregnancy test with a sensitivity of a least 25 mIU/mL) within 1 week prior to beginning therapy. WOCBP must be willing to agree to contraceptive practices as detailed in the Contraception Guidelines.
6. Negative cross match test, and compatible (A, B, AB or O) blood type.
7. Able to swallow tablets and capsules. |
|
| E.4 | Principal 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 or > 40 kg/m2, calculated using the formula of BMI = mass/(height2).
5. History of alcohol abuse with less than 6 months of sobriety.
6. History of recreational drug abuse with less than 6 months of documented abstinence.
7. Screening 12-lead ECG demonstrating clinically relevant abnormalities (including QT prolongation).
8. WOCBP who are either pregnant, lactating, planning to become pregnant or with a positive serum or urine pregnancy test.
9. Patients with an oral temperature (prior to study drug dosing) of 38 ºC (100.4 ºF) or higher.
10. Patients with clinically significant active infections (for example, those requiring hospitalization, or as judged by the Investigator) including current, latent or prior tuberculosis infection.
11. Patients with known hereditary immunodeficiency.
12. Patients with malignancies or with a history of malignancies (within the last 5 years) with the exception of local, noninvasive, fully excised: cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma, or cervical carcinoma in situ.
13. Patients who are receiving or expect to receive sirolimus, everolimus, azathioprine or cyclophosphamide within 3 months prior to enrollment.
14. Any psychiatric or medical condition (cardiac, pulmonary, CNS, GI, endocrine/metabolic, etc) that, in the investigator's opinion, may put the subject at significant risk, may confound the study results, or may interfere significantly with the subject's participation in the study.
15. Patients currently enrolled in another investigational device or drug study, and who are in the active treatment phase or are less than 30 days since treatment with the investigational agent (s).
16. Laboratory variables that are abnormal (outside laboratory reference range) and clinically relevant, as judged by the Investigator.
17. 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). Negative results for these serological tests must be documented within 12 months prior to randomization into the study.
18. Patients who experienced graft loss within 1 year of transplant, due to acute rejection or due to BK nephropathy.
19. Patients having experienced primary focal segmental glomerulosclerosis (FSGS).
20. Donor with positive serological test result for HIV-1, HBV or HCV.
21. Donor with history of malignant disease (current or historical).
22. Centers for Disease Control and Prevention high-risk donor.
23. Patients with mental dysfunction or inability to cooperate with the
study.
24. Cold ischemia time >30 hours.
25. Non-heart-beating donor. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
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.
The primary safety endpoints at Month 12 (Day 360) will include
1. Incidence of adverse events, serious adverse events, and discontinuations due to adverse events
2. incidence of the following predefined potentially clinically significant laboratory values:
- FPG level ≥ 126 mg/dL
- platelets < 100 x 10^9 cells/L
- WBC < 2.0 x 10^9 cells/L
- transaminases ≥ 100 U/L
- total cholesterol ≥ 240 mg/dL
- LDL cholesterol ≥ 190 mg/dL
- triglycerides ≥ 200 mg/dL
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints include:
1. 6-month treatment failure rates
2. 6-month and 12-month all cause mortality rates
3. 6-month and 12-month graft failure rates
4. 6-month and 12-month BPAR rates
5. 6-month and 12-month lost to follow-up rates
6. 6-month and 12-month incidences of patient death or graft failure
7. 6-month and12-month clinically suspected and treated acute rejections
8. 6-month and 12-month premature discontinuation for any reason
9. severity grades of the first episode of BPAR
10. Time to event analysis of time to death, time to graft failure, time to first episode of BPAR, and time to lost to follow-up
Secondary Safety Endpoints
Secondary safety endpoints include:
1. New-onset diabetes mellitus within 6 months and 12 months
2. Incidences of any opportunistic infection and any malignancy
3. Incidences of post-transplant lymphoproliferation disorder (PTLD) among all patients and within the patients who are EBV seronegative at the time of transplant
4. Mean change from Baseline (Day 30) in estimated creatinine clearance by estimated
glomerular flow rate (eGFR) at Months 3, 6, and 12
5. Mean dose of study drug and mean tacrolimus whole blood trough level at each post
randomization visit
6. Interpatient and intrapatient variability of tacrolimus whole blood trough levels
7. Change in clinical laboratories and vital signs at each time point
8. Incidence of 12-lead ECGs clinical findings at each time point
9. In patients not diabetic at time of transplant, mean change from (Baseline) Day 0 in
HbA1c at Days 90, 180 and 360
10. Incidence of clinically significant infection (confirmed by culture, biopsy, genomic or serologic findings) that requires hospitalization or systemic anti-infective treatment, or is otherwise deemed significant by the Investigator
11. Cytomegalovirus [CMV] disease will be assessed as 1) symptomatic CMV syndrome, 2) tissue-invasive CMV disease and 3) asymptomatic CMV).
12. Incidence of BK virus viremia at days 30, 90, 180 and 360
13. Incidence of BK virus nephropathy |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Each visit (Days 1,2,3,4,7,10,14,21,30,45,60,90,120,180,270 and 360; Month 15,18,21 and 24): vital signs measurements, AEs, tacrolimus whole blood trough concentrations, recording of concomitant medications.
Allograft rejection evaluations (inc. renal biopsy): as necessary, throughout treatment period.
Physical examinations: Days 30,90,180,360, Months 18,24
12-lead ECGs: Days 180,360, Month 18,24
Lab tests: all from Day 7* (inc. hematology, fasting blood chemistry, urinalysis, spot protein:creatinine ratio).
Serum creatinine measurements: all from Day 10*.
Fasting hepatic function profile: Days 30,180,360, Months 18,24
HbA1c: all from Day 21*
eGFR measurement: all from Day 30*
Determinations of BKV: Days 14,30 and 60 onward*
CMV: all from Day 120*
*except Day 18,20 and Month 15,21 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Brazil |
| France |
| Germany |
| Italy |
| Korea, Republic of |
| Mexico |
| New Zealand |
| Poland |
| Serbia |
| Singapore |
| Spain |
| Sweden |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last visit of the last subject |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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