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This study will assess the efficacy of everolimus as an inhibitor of fibrosis progression in liver transplant patients who have a recurrence of hepatitis C viral infection in the transplant
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| CsA-TAC | Active Comparator | Continuation of current immunosuppressive regimen (continuation of Calcineurin Inhibitor [CNI] with or without Enteric-coated mycophenolate sodium (myfortic) or mycophenolate mofetil(Cellcept)[MPA], with or without steroids) / no everolimus introduction. |
|
| everolimus | Experimental | Initiation of everolimus with discontinuation of CNI/MPA, with or without steroids. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| CsA-TAC (standard Treatment) | Drug | Continuation of current immunosuppressive regimen (continuation of CNI with or without MPA, with or without steroids) / no everolimus introduction. |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in Fibrosis Staging Score (Measured by the Ishak-Knodell Staging Score) Between Baseline and 24 Months Post-transplant. | Ishak-Knodell Score: 0=No fibrosis; 01=Fibrous expansion of some portal areas, with or without short fibrous septa; 02=Fibrous expansion of most portal areas, with or without short fibrous septa; 03=Fibrous expansion of most portal areas, with occasional portal to portal (P-P) bridging; 04=Fibrous expansion of portal areas, with marked bridging (portal to portal (P-P) as well as portal to central (P-C)); 05=Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); 06=Cirrhosis, probable or definite Decrease in score from baseline indicates improvement | baseline, 24 Months |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline in Fibrosis Metavir Scoring at 12 and 24 Months Post Randomization | Metavir Score: F0=No fibrosis; F1=Portal fibrosis without septa; F2=Portal fibrosis with rare septa; F3=Numerous septa without cirrhosis Decrease in score from baseline indicates improvement | Baseline, 12 months, 24 months |
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Inclusion Criteria:
Exclusion Criteria:
Other protocol defined inclusion/exclusion criteria may apply.
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| Name | Affiliation | Role |
|---|---|---|
| Novartis Pharmaceuticals | Novartis Pharmaceuticals | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Novartis Investigative site | Buenos Aires | Argentina |
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| ID | Title | Description |
|---|---|---|
| FG000 | Standard Treatment | Continuation of current immunosuppressive regimen (continuation of Calcineurin Inhibitor [CNI] with or without Enteric-coated mycophenolate sodium (myfortic) or mycophenolate mofetil(Cellcept)[MPA], with or without steroids) / no everolimus introduction. |
| FG001 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Everolimus | Drug | Hepatitis C recurrence after orthotopic liver transplantation (OLT) |
|
| Percentage of Patients With Death, Graft Loss and Biopsy Proven Acute Rejection (BPAR) Between Study Groups |
| 24 Months |
| Number of Patients With Events (Progression to Cirrhosis, Retransplantation, HCV Related Death, First BPAR, Graft Loss)at 12 and 24 Months | 12 months, 24 months |
| Comparison of Renal Function (Glomerular Filtration Rate [GFR] Calculated Using the Modification of Diet in Renal Disease Study Group [MDRD] Formula) Between Study Groups | GFR Month 9 value if available, otherwise minimal first year post-randomization available value. Imputation rule of missing Month 24 GFR values: GFR Month 18 value if available, otherwise Month 12 GFR is used. Least square means are from an ANCOVA model containing treatment as factor and baseline eGFR as a covariate. | 12 months, 24 months/EOS |
| Comparison of the Effect of Both Regimens in the Necroinflammatory Grading Score (Ishak-Knodell) (Portal Inflammation) | Ishak-Knodell Score: 0=No fibrosis; 01=Fibrous expansion of some portal areas, with or without short fibrous septa; 02=Fibrous expansion of most portal areas, with or without short fibrous septa; 03=Fibrous expansion of most portal areas, with occasional portal to portal (P-P) bridging; 04=Fibrous expansion of portal areas, with marked bridging (portal to portal (P-P) as well as portal to central (P-C)); 05=Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); 06=Cirrhosis, probable or definite | baseline, 12 months, 24 months |
| Comparison of the Effect of Both Regimens on the Inflammatory (Acti-test) and Fibrosis (Fibro-test) Components of Fibrosure, and on Fibrosis Area Assessed by Histomorphometry | The Fibrosure test is the combination of Fibro-test + Acti-test. FibroTest (FT) was for the assessment of fibrosis. Fibro test was calculated using an original combination of five highly concentrated serum biochemical markers; alpha2macroglobulin, haptoglobin, apolipoprotein A1, total bilirubin and gammaglutamyltransferase (GGT). FibroTest scores range from 0.00 to 1.00 where 0.0-0.21 is no fibrosis and >= 0.59 is cirrhosis. Acti-test was calculated using 6 serum biochemical markers; alpha2macroglobulin, haptoglobin, apolipoprotein A1, total bilirubin, GGT and alanine aminotransferase (ALT). ActiTest (AT) was used for the assessment of necroinflammatory activity. Test score ranges from 0.00 to 1.00, where 0.00-0.17 indicates no necrosis and >= 0.61 indicates severe necrosis If 12-month Actitest value was the last available assessment, the value is used to impute the final staging score(End of Study) | baseline, 12 and 24 months |
| Percentage of Patients in Each Study Arm With Increase of ≥1 Point in the Ishak-Knodell Staging Score in Fibrosis | Ishak-Knodell Score: 0=No fibrosis; 01=Fibrous expansion of some portal areas, with or without short fibrous septa; 02=Fibrous expansion of most portal areas, with or without short fibrous septa; 03=Fibrous expansion of most portal areas, with occasional portal to portal (P-P) bridging; 04=Fibrous expansion of portal areas, with marked bridging (portal to portal (P-P) as well as portal to central (P-C)); 05=Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); 06=Cirrhosis, probable or definite. | baseline to month 24 |
| Change From Baseline in Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Viral Load at 12 and 24 Months Post Randomization | End of Study (EOS) endpoint is the last available assessment on or after Month 12. A reduction of at least two logs in HCV RNA viral load was considered as success | baseline, 12 months, 24 months/EOS |
| Everolimus |
Initiation of everolimus with discontinuation of CNI/MPA, with or without steroids. |
| COMPLETED |
|
| NOT COMPLETED |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Standard Treatment | Continuation of current immunosuppressive regimen (continuation of Calcineurin Inhibitor [CNI] with or without Enteric-coated mycophenolate sodium (myfortic) or mycophenolate mofetil(Cellcept)[MPA], with or without steroids) / no everolimus introduction. |
| BG001 | Everolimus | Initiation of everolimus with discontinuation of CNI/MPA, with or without steroids. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age Continuous | Median | Full Range | years |
| |||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change From Baseline in Fibrosis Staging Score (Measured by the Ishak-Knodell Staging Score) Between Baseline and 24 Months Post-transplant. | Ishak-Knodell Score: 0=No fibrosis; 01=Fibrous expansion of some portal areas, with or without short fibrous septa; 02=Fibrous expansion of most portal areas, with or without short fibrous septa; 03=Fibrous expansion of most portal areas, with occasional portal to portal (P-P) bridging; 04=Fibrous expansion of portal areas, with marked bridging (portal to portal (P-P) as well as portal to central (P-C)); 05=Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); 06=Cirrhosis, probable or definite Decrease in score from baseline indicates improvement | The Intent to Treat (ITT) population consisted of all patients randomized and who had at least one dose of study medication. Small number of biopsies obtained at Month 24 due to study being prematurely terminated. | Posted | Median | Full Range | Score on Scale | baseline, 24 Months |
|
|
| ||||||||||||||||||||||||||||
| Secondary | Change From Baseline in Fibrosis Metavir Scoring at 12 and 24 Months Post Randomization | Metavir Score: F0=No fibrosis; F1=Portal fibrosis without septa; F2=Portal fibrosis with rare septa; F3=Numerous septa without cirrhosis Decrease in score from baseline indicates improvement | The Intent to Treat (ITT) population consisted of all patients randomized and who had at least one dose of study medication. Only participants with observations at baseline and specified timepoints were included in the analysis. | Posted | Median | Full Range | Scores on a Scale | Baseline, 12 months, 24 months |
|
| |||||||||||||||||||||||||||||
| Secondary | Percentage of Patients With Death, Graft Loss and Biopsy Proven Acute Rejection (BPAR) Between Study Groups | The Intent to Treat (ITT) population consisted of all patients randomized and who had at least one dose of study medication. | Posted | Number | Percentage of Participants | 24 Months |
|
| |||||||||||||||||||||||||||||||
| Secondary | Number of Patients With Events (Progression to Cirrhosis, Retransplantation, HCV Related Death, First BPAR, Graft Loss)at 12 and 24 Months | The Intent to Treat (ITT) population consisted of all patients randomized and who had at least one dose of study medication. During different time points, participants with observations at that time point were included in the analysis. | Posted | Number | participants | 12 months, 24 months |
|
| |||||||||||||||||||||||||||||||
| Secondary | Comparison of Renal Function (Glomerular Filtration Rate [GFR] Calculated Using the Modification of Diet in Renal Disease Study Group [MDRD] Formula) Between Study Groups | GFR Month 9 value if available, otherwise minimal first year post-randomization available value. Imputation rule of missing Month 24 GFR values: GFR Month 18 value if available, otherwise Month 12 GFR is used. Least square means are from an ANCOVA model containing treatment as factor and baseline eGFR as a covariate. | The Intent to Treat (ITT) population consists of all patients randomized and who have at least one dose of study medication. During different time points, participants with observations at that time point were included in the analysis. | Posted | Least Squares Mean | Standard Error | mL/min/1.73^2 | 12 months, 24 months/EOS |
| ||||||||||||||||||||||||||||||
| Secondary | Comparison of the Effect of Both Regimens in the Necroinflammatory Grading Score (Ishak-Knodell) (Portal Inflammation) | Ishak-Knodell Score: 0=No fibrosis; 01=Fibrous expansion of some portal areas, with or without short fibrous septa; 02=Fibrous expansion of most portal areas, with or without short fibrous septa; 03=Fibrous expansion of most portal areas, with occasional portal to portal (P-P) bridging; 04=Fibrous expansion of portal areas, with marked bridging (portal to portal (P-P) as well as portal to central (P-C)); 05=Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); 06=Cirrhosis, probable or definite | The Intent to Treat (ITT) population consists of all patients randomized and who have at least one dose of study medication. During different time points, participants with observations at that time point were included in the analysis. | Posted | Mean | Standard Deviation | Score on a scale | baseline, 12 months, 24 months |
| ||||||||||||||||||||||||||||||
| Secondary | Comparison of the Effect of Both Regimens on the Inflammatory (Acti-test) and Fibrosis (Fibro-test) Components of Fibrosure, and on Fibrosis Area Assessed by Histomorphometry | The Fibrosure test is the combination of Fibro-test + Acti-test. FibroTest (FT) was for the assessment of fibrosis. Fibro test was calculated using an original combination of five highly concentrated serum biochemical markers; alpha2macroglobulin, haptoglobin, apolipoprotein A1, total bilirubin and gammaglutamyltransferase (GGT). FibroTest scores range from 0.00 to 1.00 where 0.0-0.21 is no fibrosis and >= 0.59 is cirrhosis. Acti-test was calculated using 6 serum biochemical markers; alpha2macroglobulin, haptoglobin, apolipoprotein A1, total bilirubin, GGT and alanine aminotransferase (ALT). ActiTest (AT) was used for the assessment of necroinflammatory activity. Test score ranges from 0.00 to 1.00, where 0.00-0.17 indicates no necrosis and >= 0.61 indicates severe necrosis If 12-month Actitest value was the last available assessment, the value is used to impute the final staging score(End of Study) | The Intent to Treat (ITT) population consists of all patients randomized and who have at least one dose of study medication. During different time points, participants with observations at that time point were included in the analysis. | Posted | Median | Full Range | units on a scale | baseline, 12 and 24 months |
| ||||||||||||||||||||||||||||||
| Secondary | Percentage of Patients in Each Study Arm With Increase of ≥1 Point in the Ishak-Knodell Staging Score in Fibrosis | Ishak-Knodell Score: 0=No fibrosis; 01=Fibrous expansion of some portal areas, with or without short fibrous septa; 02=Fibrous expansion of most portal areas, with or without short fibrous septa; 03=Fibrous expansion of most portal areas, with occasional portal to portal (P-P) bridging; 04=Fibrous expansion of portal areas, with marked bridging (portal to portal (P-P) as well as portal to central (P-C)); 05=Marked bridging (P-P and/or P-C) with occasional nodules (incomplete cirrhosis); 06=Cirrhosis, probable or definite. | Difference Ishak-Knodell Score at End-of-Study The Intent to Treat (ITT) population consists of all patients randomized and who have at least one dose of study medication | Posted | Number | percentage of participants | baseline to month 24 |
| |||||||||||||||||||||||||||||||
| Secondary | Change From Baseline in Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) Viral Load at 12 and 24 Months Post Randomization | End of Study (EOS) endpoint is the last available assessment on or after Month 12. A reduction of at least two logs in HCV RNA viral load was considered as success | The Intent to Treat (ITT) population consists of all patients randomized and who have at least one dose of study medication. If 12-month HCV was the last available assessment, this value is used to impute the End of Study value. | Posted | Mean | Standard Deviation | log10 copies/ml | baseline, 12 months, 24 months/EOS |
|
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | CsA/TAC | Continuation of current immunosuppressive regimen (continuation of CNI with or without MPA, with or without steroids) / no everolimus introduction. | 0 | 21 | 8 | 21 | ||
| EG001 | EVR (Everolimus) | Initiation of everolimus with discontinuation of CNI/MPA, with or without steroids. | 11 | 22 | 20 | 22 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cardio-respiratory arrest | Cardiac disorders | MedDRA | Systematic Assessment |
| |
| Tachyarrhythmia | Cardiac disorders | MedDRA | Systematic Assessment |
| |
| Abdominal hernia | Gastrointestinal disorders | MedDRA | Systematic Assessment |
| |
| Ascites | Gastrointestinal disorders | MedDRA | Systematic Assessment |
| |
| Cholangitis | Hepatobiliary disorders | MedDRA | Systematic Assessment |
| |
| Gastroenteritis | Infections and infestations | MedDRA | Systematic Assessment |
| |
| Hepatitis C | Infections and infestations | MedDRA | Systematic Assessment |
| |
| Pneumonia | Infections and infestations | MedDRA | Systematic Assessment |
| |
| Sepsis | Infections and infestations | MedDRA | Systematic Assessment |
| |
| Wound infection | Infections and infestations | MedDRA | Systematic Assessment |
| |
| Hepatic haematoma | Injury, poisoning and procedural complications | MedDRA | Systematic Assessment |
| |
| Transaminases increased | Investigations | MedDRA | Systematic Assessment |
| |
| Musculoskeletal chest pain | Musculoskeletal and connective tissue disorders | MedDRA | Systematic Assessment |
| |
| Ischaemic stroke | Nervous system disorders | MedDRA | Systematic Assessment |
| |
| Renal failure | Renal and urinary disorders | MedDRA | Systematic Assessment |
| |
| Erectile dysfunction | Reproductive system and breast disorders | MedDRA | Systematic Assessment |
| |
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
| |
| Pneumonitis | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
| |
| Respiratory tract congestion | Respiratory, thoracic and mediastinal disorders | MedDRA | Systematic Assessment |
|
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Leukopenia | Blood and lymphatic system disorders | MedDRA | Systematic Assessment |
| |
| Aphthous stomatitis | Gastrointestinal disorders | MedDRA | Systematic Assessment |
| |
| Diarrhoea | Gastrointestinal disorders | MedDRA | Systematic Assessment |
| |
| Mouth ulceration | Gastrointestinal disorders | MedDRA | Systematic Assessment |
| |
| Stomatitis | Gastrointestinal disorders | MedDRA | Systematic Assessment |
| |
| Pyrexia | General disorders | MedDRA | Systematic Assessment |
| |
| Cholelithiasis | Hepatobiliary disorders | MedDRA | Systematic Assessment |
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| Bronchitis | Infections and infestations | MedDRA | Systematic Assessment |
| |
| Influenza | Infections and infestations | MedDRA | Systematic Assessment |
| |
| Upper respiratory tract infection | Infections and infestations | MedDRA | Systematic Assessment |
| |
| Blood cholesterol increased | Investigations | MedDRA | Systematic Assessment |
| |
| Blood triglycerides increased | Investigations | MedDRA | Systematic Assessment |
| |
| Blood uric acid abnormal | Investigations | MedDRA | Systematic Assessment |
| |
| Blood uric acid increased | Investigations | MedDRA | Systematic Assessment |
| |
| Liver function test abnormal | Investigations | MedDRA | Systematic Assessment |
| |
| Platelet count decreased | Investigations | MedDRA | Systematic Assessment |
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| Dyslipidaemia | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
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| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
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| Hypertriglyceridaemia | Metabolism and nutrition disorders | MedDRA | Systematic Assessment |
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| Proteinuria | Renal and urinary disorders | MedDRA | Systematic Assessment |
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| Renal impairment | Renal and urinary disorders | MedDRA | Systematic Assessment |
| |
| Erythema | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
| |
| Pruritus | Skin and subcutaneous tissue disorders | MedDRA | Systematic Assessment |
| |
| Hypertension | Vascular disorders | MedDRA | Systematic Assessment |
|
The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (i.e., data from all sites) in the clinical trial.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Novartis | Pharmaceuticals | 41613241111 |
| ID | Term |
|---|---|
| D006526 | Hepatitis C |
| D014777 | Virus Diseases |
| ID | Term |
|---|---|
| D000086982 | Blood-Borne Infections |
| D003141 | Communicable Diseases |
| D007239 | Infections |
| D006525 | Hepatitis, Viral, Human |
| D018178 | Flaviviridae Infections |
| D012327 | RNA Virus Infections |
| D006505 | Hepatitis |
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D000068338 | Everolimus |
| ID | Term |
|---|---|
| D020123 | Sirolimus |
| D018942 | Macrolides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
Not provided
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| Male |
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| Units |
|---|
| Counts |
|---|
| Participants |
|
|
| Units | Counts |
|---|---|
| Participants |
|
|
| OG001 | Everolimus -Summary of Actitest by Treatment | Initiation of everolimus with discontinuation of CNI/MPA, with or without steroids. |
| OG002 | Standard Treatment -Summary of Fibrotest by Treatment | Continuation of current immunosuppressive regimen (continuation of Calcineurin Inhibitor [CNI] with or without Enteric-coated mycophenolate sodium (myfortic) or mycophenolate mofetil(Cellcept)[MPA], with or without steroids) / no everolimus introduction. |
| OG003 | Everolimus - Summary of Fibrotest by Treatment | Initiation of everolimus with discontinuation of CNI/MPA, with or without steroids. |
|
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| Units | Counts |
|---|---|
| Participants |
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