| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Liver allograft recipients under maintenance therapy |
|
| MedDRA Classification |
| 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 demonstrate the following in stable transplant recipients:
a) Superiority of the sirolimus (SRL) conversion regimen over the calcineurin inhibitor (CI) continuation regimen with regard to the change from baseline in calculated glomerular filtration rate (GFR, Cockcroft-Gault method) at 12 months. The comparison will be performed on an intent-to-treat (ITT) basis (incorporating calculated GFRs for all subjects for whom a 12-month creatinine value is available).
b) Non-inferiority of the SRL conversion regimen with regard to the rate of the first occurence of graft loss or death at 12 months in the ITT population. |
|
| E.2.2 | Secondary objectives of the trial |
To compare the following between the 2 treatment groups:
a) incidence of biopsy-confirmed acute rejection
b) subject and graft survival
c) change in creatinine values in the ITT and on-therapy populations
d) GFR values calculated by the methods of Cockcroft-Gault and Levey and measured GFR values for the ITT and on-therapy population
e) slope of the regression line for a plot of 1/creatinine and GFR values versus time
f) incidence of treatment failure (defined as the first occurence of acute rejection or premature discontinuation from treatment for any reason)
g) mean systolic and diastolic blood pressures and mean arterial pressure
h) percentage of subjects requiring treatment for hypertension and number of antihypertensive agents used
i) quality of life outcomes
j) change in the hepatic fibrosis score over time
k) incidence of malignancy and infection
l) long term safety for up to 6 years |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Age >=13 years (>=18 years in Austria, Czech Republic, Denmark, Finland, France, Germany, Norway, Poland, Sweden, Switzerland, United Kingdom and as required by local regulation or ethical committees) and weight >=40 kg.
2. Women of childbearing potential must have a negative serum pregnancy test result before random assignment and must agree to use a medically acceptable method of contraception throughout the treatment period and for 3 months after discontinuation of randomly assigned treatment. Any woman becoming pregnant during the treatment period must withdraw from the study.
3. Subjects receiving immunosuppressive therapy with a stable regimen of CI or a combination of CI with CS and/or antimetabolite therapy for a minimum of 4 weeks prior to randomization.
4. Treatment with the same CI for at least 4 weeks before random assignment.
5. Six (6) to 144 months after orthotopic liver transplantation.
6. Cockcroft-Gault GFR values >=40 mL/min and <=90 mL/min at screening.
7. Doppler ultrasound performed within 4 weeks before random assignment showing no evidence of thrombosis or of clinically significant stenosis of hepatic artery, hepatic vein, or portal vein.
8. Total white blood cell count >3.0 x 10 9/L (>3,000/mm3), platelet count >75 x 10 9/L (>75,000/mm3 ), fasting triglycerides <3.95 mmol/L (<350 mg/dL), fasting cholesterol <7.8 mmol/L (<300 mg/dL). If subjects are currently untreated for elevated cholesterol and/or triglycerides and are excluded from the study based on the above criteria, subjects may be initiated on antihyperlipidemic therapy and re-screened.
9. Liver function test (LFT) results (ie, aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin, and alkaline phosphatase) <3 times the upper limit of normal on 2 consecutive determinations within 3 months before random assignment. For subjects who are Hepatitis C positive (determined by PCR), AST and ALT values must be < 5 times the upper limit of normal on 2 consecutive determinations within 3 months before random assignment.
10. Subjects with any LFT (AST, ALT, total bilirubin, or alkaline phosphatase) >2 times the upper limit of normal (on 2 consecutive determinations within 3 months before random assignment) must have a liver biopsy performed within 3 months before random assignment showing no evidence of acute rejection unless a clear alternative etiology is apparent for elevated LFTs.
Subjects who are Hepatitis C positive (determined by PCR) with total bilirubin or alkaline phosphatase values > 2 times the upper limit of normal on 2 consecutive determinations less than 3 months before random assignment, must have a liver biopsy performed less than 3 months before random assignment to exclude rejection unless a clear alternative etiology for elevated LFT(s) is apparent. Prior discussion with the medical monitor about the alternative etiology is required before randomizing any patient who meets this criteria.
11. All Hepatitis C positive subjects (as determined by PCR) must have a liver biopsy performed within 6 months before random assignment showing no evidence of acute rejection or Liver Fibrosis score 4, 5 or 6 (Banff 1997) or correlating Metavir score of F3 or F4 (See Attachment 10).
12. Subjects undergoing therapy for Hepatitis C infection who completed a full course of therapy must be at least 6 months post therapy. Subjects who were non-responders or who failed HCV therapy, must be at least 4 weeks post discontinuation of therapy (See Screening and Evaluating for Hepatitis C Virus Status in section 11 of the synopsis and Study Flowchart 6).
13. Subjects who had malignant liver tumors (primary hepatocellular carcinoma) discovered incidentally at the time of transplantation or coincidentally before transplantation may be enrolled if they had 1) a primary solitary liver tumor of less than 5 cm or 2) 3 or fewer lesions with none exceeding 3 cm in diameter, without extrahepatic metastases.
14. Subjects with malignant liver tumors (primary hepatocellular carcinoma) that were treated with chemoembolization or radiofrequency ablation before transplantation and who meet the above criteria may be enrolled unless systemic chemotherapy was/is being administered. However, patients may be enrolled if post-transplant prophylactic chemotherapy was discontinued > 6 months before random assignment.
15. Written, signed, and dated IRB- or IEC-approved informed consent (subjects younger than the legal age of consent will sign an assent form, but a parent or legal guardian must provide written permission). |
|
| E.4 | Principal exclusion criteria |
1. History of nonhepatic transplantation.
2. Serum creatinine at the time of screening that has increased > 30% above the last value obtained at least 8 weeks prior to screening. Subjects with values that deviate from this exclusion criterion may be enrolled only with the approval of the Wyeth Research (WR) global medical monitor.
3. Concomitant therapy with an immunosuppressive agent other than CI, CS, or antimetabolite therapy (MMF or AZA) within 4 weeks before random assignment.
4. Evidence of systemic infection (ie, sepsis, bacteremia, pneumonia, etc.) at time of random assignment.
5. Biopsy performed within 3 months before random assignment showing Banff 1997 grade I or II acute rejection or biopsy performed within 12 months before random assignment showing grade III rejection.
6. Any treatment for suspected or biopsy-confirmed acute rejection within 3 months before random assignment or treatment with anti-lymphocyte antibody for suspected or biopsy-confirmed acute rejection within 12 months before random assignment.
7. Stage 4, 5 or 6 hepatic fibrosis score using Banff 1997 scoring criteria or correlating Metavir fibrosis grade F3 or F4 on any posttransplant biopsy and/or in the opinion of the investigators, signs of decompensated liver disease of the current liver allograft.
8. Therapy for recurrent Hepatitis B infection received within 4 weeks before random assignment (excluding approved prophylaxis).
9. Known or suspected malignancy <= 5 years before random assignment (with the exception of adequately treated basal cell or squamous cell carcinomas of the skin or malignant liver tumors [primary hepatocellular carcinoma] as specified in inclusion criteria 13 and 14).
10. History of posttransplant lymphoproliferative disease.
11. Use of any investigational drugs within 4 weeks before random assignment.
12. Prior or current use of SRL or any of its derivatives (unless prior approval from WR medical monitor).
13. Treatment with any renal replacement therapy within 2 weeks before random assignment.
14. Presence of unstable angina or use of ongoing maintenance therapy for a life-threatening arrhythmia.
15. History of documented human immunodeficiency virus infection.
16. Hypercoagulable states or any history of deep vein thrombosis, HAT, or portal vein thrombosis . (Exception: incidental vascular thrombosis at time of liver explant which, in the opinion of the investigator, does not place the subject at increased risk of thrombotic event).
17. Requirement for the administration of terfenadine, cisapride, pimozide, astemizole, (oral) ketoconazole, voriconazole or cimetidine after random assignment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. The change from baseline in calculated GFR (Cockcroft-Gault method) at 12 months in the ITT population (incorporating calculated GFRs for all subjects for whom a month 12 creatinine value is available).
2. The rate of the first occurrence of graft loss or death at 12 months in the ITT population. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| 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 | Information not present in EudraCT |
| 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| 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.8.3 |
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.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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
|
The study is expected to be completed with the last visit of the last subject. However Wyeth Research may terminate the study at any time for any of the following reasons:
1. Failure to enroll subjects.
2. Protocol violations.
3. Inaccurate or incomplete data.
4. Unsafe or unthetical practices.
5. Questionable safety of the test article.
6. Suspected lack of efficacy of the test article.
7. Marketing authorization in the respective region or country.
8. Administrative decision. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 85 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 85 |
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