Liver allograft recipients under maintenance therapy
Conditions
Interventions
Trade Name: Rapamune 1mg coated tablets
Product Name: Rapamune 1mg
Pharmaceutical Form: Coated tablet
INN or Proposed INN: sirolimus
CAS Number: 53123-88-9
Current Sponsor code: 0468
Other descriptive
Sponsors
Wyeth Research Division of Wyeth Pharmaceuticals Inc.Clinical Research & Development Department
Eligibility
Sex/Gender
All
Inclusion criteria
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 3.0 x 10 9/L (>3,000/mm3), platelet count >75 x 10 9/L (>75,000/mm3 ), fasting triglycerides 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
Exclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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.;Secondary Objective: 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 ;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. | — |
Countries
Czech Republic
Outcome results
None listed