Hepatitis C, Liver Transplantation
Conditions
Keywords
Hepatitis C, liver transplantation, anti-viral therapy
Brief summary
This study will assess the rates of Sustained Virological Response following anti-viral therapy with Peg-Interferon plus Ribavirin in patients that have been liver transplanted with recurrent Hepatitis C and treated with Neoral or tacrolimus.
Interventions
DRUGcyclosporin (Neoral)
Neoral capsules bid, Doses were to be adjusted as necessary to achieve and maintain recommended C0 (monitoring of trough levels) or C2 concentration 2 hours post dosing) target ranges
Tacrolimus capsules bid, doses were adjusted as necessary to achieve and maintain recommended C0 target ranges.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Liver transplantation performed at least 6 months and up to 5 years prior randomization and due to HCV cirrhosis, with or without pre-transplant hepatocellular carcinoma (HCC) within Milan or UCSF criteria * Immunosuppresive regimen based on tacrolimus b.i.d.- (twice or once daily) for at least 6 months prior randomization * Diagnosis of HCV genotypes 1 or 4 infection prior to transplantationconfirmed at screening * Indication of treatment with Peg-IFN and ribavirin due to histological evidence of chronic HCV infection defined as a fibrosis stage equal or greater than 1 using the Ishak-Knodell scoring system (IK ≥1) in a liver biopsy performed at screening or up to 4 months prior to randomization.
Exclusion criteria
* Serum creatinine \>150 μmol/L (1.6 7 mg/dL) or eGFR \< 50 ml/min (4-variable Modification of Diet in Renal Disease \[MDRD Cockcroft-Gault formula\]) * Multi-organ transplant recipients * Recent episode of steroid-treated acute rejection (AR) within 3 months prior to randomization, or \>1 episode of steroid-treated AR in the last 6 months, or any number of steroid-resistant AR episodes in the last 6 months including evidence of chronic rejection or ductopenia * Evidence of conditions that could cause graft dysfunction other than HCV infection * Patients with signs of decompensated liver disease, defined as presence of ascites, variceal bleeding, encephalopathy or deteriorated hepatic synthetic function (albumin \<3.5g/dL or, total direct bilirubin \>1.5mg/dL or, INR \>1.5) * Co-infection with HIV or Hepatitis B (defined as HBsAg-positive) at screening * Use of mTOR inhibitors (everolimus or sirolimus) in the 6 months prior to screening * Antiviral treatment for HCV administered at any time after liver transplantation * Patients on daily doses of corticosteroids higher than 5 mg/day * Patients with fibrosing cholestatic hepatitis * Patients with current diagnosis of malignancies, including lymphoproliferative disorders * Patients with platelet count \<70,000/mm3 or neutrophiles \<1,500/mm3 * History of HCC outside Milan criteria based on radiology or UCSF criteria based on analysis of the explant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Sustained Virological Response (SVR) Following Treatment of Hepatitis C Virus (HCV) Infection With Peg-IFN and Ribavirin in Liver Transplanted Recipients on Maintenance Therapy With Neoral or Tacrolimus | Week 24 | The achievement of SVR, defined as HCV RNA below limit of detection at the end of AV treatment, 24 weeks after end of AV treatment (W24 post). A dichotomous variable (SVR achieved: Yes/No) was computed. A patient was classified as non-responder (SVR not achieved) if HCV RNA was detectable at the completion of antiviral treatment, at W24post, or at any time between W24 and completion of antiviral treatment. The HCV RNA detection limit was \<15 IU/ml (\<1.18 log IU/ml) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Fibrosis Progression (Increase in Ishak-Knodell (IK) Score by at Least One Point From the Baseline) | Week 80 | 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, Participants showing an increase of Ishak Knodell fibrosis score by at least one level (increase of ≥1) |
| Number of Participants of Rapid Viral Response (RVR) | Week 4 | RVR defined as non-detectable HCV RNA 4 weeks after initiation of antiviral treatment. The HCV RNA detection limit was \<15 IU/ml (\<1.18 log IU/ml) |
| Number of Participants of Early Viral Response (EVR) | Week 12 | EVR defined as non-detectable HCV RNA or a ≥2 logs reduction of HCV RNA at 12 weeks after initiation of antiviral treatment. The HCV RNA detection limit was \<15 IU/ml (\<1.18 log IU/ml) |
| Number of Events of the Composite Endpoint of Biopsy Proven Acute Rejections (BPAR), Death or Graft Loss and of the Individual Components | Week 80 | Efficacy failure (biopsy proven acute rejection (BPAR), graft loss, or death |
| Number of Participants of True Non-responder Rate | Week 80 | Defined as failure to achieve at least a 2 log reduction of Hepatitis C virus (HCV) RNA. The HCV RNA detection limit was \<15 IU/ml (\<1.18 log IU/ml) |
| Number of Participants for Relapse Rate | Week 24 | Defined as reappearance of detectable Hepatitis C Virus (HCV) RNA at 24 weeks after completion of antiviral treatment when HCV RNA was undetectable at the end of treatment. The HCV RNA detection limit was \<15 IU/ml (\<1.18 log IU/ml) |
| Number of Participants With Dose Reduction or Discontinuation of Antiviral (AV) Therapy Due to Poor Tolerability at Any Time During the Study for Any Reason | Week 80 | Defined as number of patients with dose reduction or discontinuation of AV therapy due to poor tolerability |
| Number of Participants for the End of Treatment Response (ETR) | Week 80 | ETR defined as non-detectable HCV RNA at the completion of AV treatment. The HCV RNA detection limit was \<15 IU/ml (\<1.18 log IU/ml) |
Countries
Belgium, Brazil, Canada, Colombia, France, Germany, Italy, Russia, South Korea, Spain, Switzerland, United Kingdom, United States
Participant flow
Pre-assignment details
This was an 80 week multicenter randomized, open label, controlled study in adult HCVpositive maintenance liver transplant recipients. Patients were randomized at a 1.3:1 ratio to CsA and tacrolimus. Patients randomized to tacrolimus were maintained on treatment with tacrolimus, patients randomized to CsA were converted from tacrolimus to CsA
Participants by arm
| Arm | Count |
|---|---|
| Neoral Neoral® (cyclosporine for microemulsion), available as 10 mg, 25 mg, 50 mg and 100 mg soft gelatin capsules taken on a twice daily (b.i.d) schedule at 12-hour intervals, Doses were to be adjusted as necessary to achieve and maintain recommended C0 (monitoring of trough levels) or C2 concentration 2 hours post dosing) target ranges | 50 |
| Tacrolimus Prograf® (tacrolimus) provided as 0.5 mg, 1 mg and 5 mg capsules taken on a twice daily (b.i.d) schedule at 12-hour intervals. Doses were adjusted as necessary to achieve and maintain recommended C0 target ranges | 42 |
| Total | 92 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal laboratory values | 2 | 2 |
| Overall Study | Administration problems | 2 | 0 |
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Lost to Follow-up | 4 | 4 |
| Overall Study | Protocol Violation | 3 | 1 |
| Overall Study | Withdrawal by Subject | 11 | 8 |
Baseline characteristics
| Characteristic | Neoral | Tacrolimus | Total |
|---|---|---|---|
| Age, Continuous | 54.2 Years STANDARD_DEVIATION 6.3 | 55.0 Years STANDARD_DEVIATION 6.84 | 54.6 Years STANDARD_DEVIATION 6.53 |
| Sex: Female, Male Female | 9 Participants | 8 Participants | 17 Participants |
| Sex: Female, Male Male | 41 Participants | 34 Participants | 75 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 41 / 42 | 42 / 50 |
| serious Total, serious adverse events | 17 / 42 | 18 / 50 |
Outcome results
Primary
Number of Participants Sustained Virological Response (SVR) Following Treatment of Hepatitis C Virus (HCV) Infection With Peg-IFN and Ribavirin in Liver Transplanted Recipients on Maintenance Therapy With Neoral or Tacrolimus
The achievement of SVR, defined as HCV RNA below limit of detection at the end of AV treatment, 24 weeks after end of AV treatment (W24 post). A dichotomous variable (SVR achieved: Yes/No) was computed. A patient was classified as non-responder (SVR not achieved) if HCV RNA was detectable at the completion of antiviral treatment, at W24post, or at any time between W24 and completion of antiviral treatment. The HCV RNA detection limit was \<15 IU/ml (\<1.18 log IU/ml)
Time frame: Week 24
Population: The efficacy population was defined as a subset of the ITT population with sufficient compliance to the protocol procedures to allow meaningful conclusions. Patients were excluded from the Efficacy population in case of: Error in treatment assignment, if the randomized study medication was not initiated, antiviral therapy was not initiated
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neoral | Number of Participants Sustained Virological Response (SVR) Following Treatment of Hepatitis C Virus (HCV) Infection With Peg-IFN and Ribavirin in Liver Transplanted Recipients on Maintenance Therapy With Neoral or Tacrolimus | 12 Participants |
| Tacrolimus | Number of Participants Sustained Virological Response (SVR) Following Treatment of Hepatitis C Virus (HCV) Infection With Peg-IFN and Ribavirin in Liver Transplanted Recipients on Maintenance Therapy With Neoral or Tacrolimus | 10 Participants |
Secondary
Number of Events of the Composite Endpoint of Biopsy Proven Acute Rejections (BPAR), Death or Graft Loss and of the Individual Components
Efficacy failure (biopsy proven acute rejection (BPAR), graft loss, or death
Time frame: Week 80
Population: Intent-to-Treat (ITT) population: The ITT population consisted of all randomized patients. Following the intent-to-treat principle, patients were analyzed according to the treatment they were assigned to at randomization.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Neoral | Number of Events of the Composite Endpoint of Biopsy Proven Acute Rejections (BPAR), Death or Graft Loss and of the Individual Components | Death | 1 Number of events |
| Neoral | Number of Events of the Composite Endpoint of Biopsy Proven Acute Rejections (BPAR), Death or Graft Loss and of the Individual Components | BPAR | 1 Number of events |
| Neoral | Number of Events of the Composite Endpoint of Biopsy Proven Acute Rejections (BPAR), Death or Graft Loss and of the Individual Components | Graft loss or death | 1 Number of events |
| Neoral | Number of Events of the Composite Endpoint of Biopsy Proven Acute Rejections (BPAR), Death or Graft Loss and of the Individual Components | BPAR, graft loss, or death | 2 Number of events |
| Tacrolimus | Number of Events of the Composite Endpoint of Biopsy Proven Acute Rejections (BPAR), Death or Graft Loss and of the Individual Components | Death | 1 Number of events |
| Tacrolimus | Number of Events of the Composite Endpoint of Biopsy Proven Acute Rejections (BPAR), Death or Graft Loss and of the Individual Components | BPAR, graft loss, or death | 1 Number of events |
| Tacrolimus | Number of Events of the Composite Endpoint of Biopsy Proven Acute Rejections (BPAR), Death or Graft Loss and of the Individual Components | Graft loss or death | 1 Number of events |
| Tacrolimus | Number of Events of the Composite Endpoint of Biopsy Proven Acute Rejections (BPAR), Death or Graft Loss and of the Individual Components | BPAR | 0 Number of events |
Secondary
Number of Participants for Relapse Rate
Defined as reappearance of detectable Hepatitis C Virus (HCV) RNA at 24 weeks after completion of antiviral treatment when HCV RNA was undetectable at the end of treatment. The HCV RNA detection limit was \<15 IU/ml (\<1.18 log IU/ml)
Time frame: Week 24
Population: The efficacy population was defined as a subset of the ITT population with sufficient compliance to the protocol procedures to allow meaningful conclusions. Patients were excluded from the Efficacy population in case of: Error in treatment assignment, if the randomized study medication was not initiated, antiviral therapy was not initiated
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neoral | Number of Participants for Relapse Rate | 5 Participants |
| Tacrolimus | Number of Participants for Relapse Rate | 7 Participants |
Secondary
Number of Participants for the End of Treatment Response (ETR)
ETR defined as non-detectable HCV RNA at the completion of AV treatment. The HCV RNA detection limit was \<15 IU/ml (\<1.18 log IU/ml)
Time frame: Week 80
Population: The efficacy population was defined as a subset of the ITT population with sufficient compliance to the protocol procedures to allow meaningful conclusions. Patients were excluded from the Efficacy population in case of: Error in treatment assignment, if the randomized study medication was not initiated, antiviral therapy was not initiated
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neoral | Number of Participants for the End of Treatment Response (ETR) | 24 Participants |
| Tacrolimus | Number of Participants for the End of Treatment Response (ETR) | 27 Participants |
Secondary
Number of Participants of Early Viral Response (EVR)
EVR defined as non-detectable HCV RNA or a ≥2 logs reduction of HCV RNA at 12 weeks after initiation of antiviral treatment. The HCV RNA detection limit was \<15 IU/ml (\<1.18 log IU/ml)
Time frame: Week 12
Population: The efficacy population was defined as a subset of the ITT population with sufficient compliance to the protocol procedures to allow meaningful conclusions. Patients were excluded from the Efficacy population in case of: Error in treatment assignment, if the randomized study medication was not initiated, antiviral therapy was not initiated
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neoral | Number of Participants of Early Viral Response (EVR) | 28 Participants |
| Tacrolimus | Number of Participants of Early Viral Response (EVR) | 30 Participants |
Secondary
Number of Participants of Rapid Viral Response (RVR)
RVR defined as non-detectable HCV RNA 4 weeks after initiation of antiviral treatment. The HCV RNA detection limit was \<15 IU/ml (\<1.18 log IU/ml)
Time frame: Week 4
Population: The efficacy population was defined as a subset of the ITT population with sufficient compliance to the protocol procedures to allow meaningful conclusions. Patients were excluded from the Efficacy population in case of: Error in treatment assignment, if the randomized study medication was not initiated, antiviral therapy was not initiated
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neoral | Number of Participants of Rapid Viral Response (RVR) | 4 Participants |
| Tacrolimus | Number of Participants of Rapid Viral Response (RVR) | 5 Participants |
Secondary
Number of Participants of True Non-responder Rate
Defined as failure to achieve at least a 2 log reduction of Hepatitis C virus (HCV) RNA. The HCV RNA detection limit was \<15 IU/ml (\<1.18 log IU/ml)
Time frame: Week 80
Population: The efficacy population was defined as a subset of the ITT population with sufficient compliance to the protocol procedures to allow meaningful conclusions. Patients were excluded from the Efficacy population in case of: Error in treatment assignment, if the randomized study medication was not initiated, antiviral therapy was not initiated
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neoral | Number of Participants of True Non-responder Rate | 7 Participants |
| Tacrolimus | Number of Participants of True Non-responder Rate | 5 Participants |
Secondary
Number of Participants With Dose Reduction or Discontinuation of Antiviral (AV) Therapy Due to Poor Tolerability at Any Time During the Study for Any Reason
Defined as number of patients with dose reduction or discontinuation of AV therapy due to poor tolerability
Time frame: Week 80
Population: The efficacy population was defined as a subset of the ITT population with sufficient compliance to the protocol procedures to allow meaningful conclusions. Patients were excluded from the Efficacy population in case of: Error in treatment assignment, if the randomized study medication was not initiated, antiviral therapy was not initiated
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Neoral | Number of Participants With Dose Reduction or Discontinuation of Antiviral (AV) Therapy Due to Poor Tolerability at Any Time During the Study for Any Reason | Tacrolimus Antiviral treatment: Peg-IFN | 0 Participants |
| Neoral | Number of Participants With Dose Reduction or Discontinuation of Antiviral (AV) Therapy Due to Poor Tolerability at Any Time During the Study for Any Reason | Neoral Antiviral treatment: Ribavirin | 25 Participants |
| Neoral | Number of Participants With Dose Reduction or Discontinuation of Antiviral (AV) Therapy Due to Poor Tolerability at Any Time During the Study for Any Reason | Neoral Antiviral treatment: Peg-IFN | 10 Participants |
| Neoral | Number of Participants With Dose Reduction or Discontinuation of Antiviral (AV) Therapy Due to Poor Tolerability at Any Time During the Study for Any Reason | Tacrolimus Antiviral treatment: Ribavirin | 0 Participants |
| Tacrolimus | Number of Participants With Dose Reduction or Discontinuation of Antiviral (AV) Therapy Due to Poor Tolerability at Any Time During the Study for Any Reason | Tacrolimus Antiviral treatment: Ribavirin | 23 Participants |
| Tacrolimus | Number of Participants With Dose Reduction or Discontinuation of Antiviral (AV) Therapy Due to Poor Tolerability at Any Time During the Study for Any Reason | Tacrolimus Antiviral treatment: Peg-IFN | 11 Participants |
| Tacrolimus | Number of Participants With Dose Reduction or Discontinuation of Antiviral (AV) Therapy Due to Poor Tolerability at Any Time During the Study for Any Reason | Neoral Antiviral treatment: Peg-IFN | 0 Participants |
| Tacrolimus | Number of Participants With Dose Reduction or Discontinuation of Antiviral (AV) Therapy Due to Poor Tolerability at Any Time During the Study for Any Reason | Neoral Antiviral treatment: Ribavirin | 0 Participants |
Secondary
Number of Participants With Fibrosis Progression (Increase in Ishak-Knodell (IK) Score by at Least One Point From the Baseline)
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, Participants showing an increase of Ishak Knodell fibrosis score by at least one level (increase of ≥1)
Time frame: Week 80
Population: The efficacy population was defined as a subset of the ITT population with sufficient compliance to the protocol procedures to allow meaningful conclusions. Patients were excluded from the Efficacy population in case of: Error in treatment assignment, if the randomized study medication was not initiated, antiviral therapy was not initiated
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neoral | Number of Participants With Fibrosis Progression (Increase in Ishak-Knodell (IK) Score by at Least One Point From the Baseline) | 3 Participants |
| Tacrolimus | Number of Participants With Fibrosis Progression (Increase in Ishak-Knodell (IK) Score by at Least One Point From the Baseline) | 5 Participants |