Liver Fibrosis in Patients Transplanted for Hepatitis C Receiving Either Cyclosporine Microemulsion or Tacrolimus

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Primary Purpose

Status

Terminated

Phase

Phase 4

Locations

International

Study Type

Interventional

Intervention

Cyclosporine A

Tacrolimus

About this trial

This is an interventional prevention trial for Liver Transplant focused on measuring Liver transplant, adults, hepatitis C, liver fibrosis, cyclosporine microemulsion, tacrolimus

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria Reason for transplant is end-stage liver disease due to hepatitis C cirrhosis Patients receiving a first liver transplant from a deceased or living donor Patients in whom biopsies will be possible Exclusion criteria Recipients of a liver from an hepatitis C virus positive (HCV+), human immunodeficiency virus positive (HIV+) or hepatitis B virus positive (HBV+) donor Patients with any severe coexisting disease or suffering any unstable medical condition or co-infected with HBV or HIV Patients with co-existing alcoholic disease who have not been abstinent for at least 6 months Transplanted for liver cancer exceeding a pre-defined size Pregnant or nursing women Other protocol-defined inclusion/exclusion criteria may apply

Sites / Locations

Novartis Investigative Site
Novartis Investigational Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

Cyclosporin A

Tacrolimus

Arm Description

The first administration of Cyclosporin A (CsA) was within the first 24 hours post-transplantation at an initial dose of 10-15mg/kg/day either orally, via a nasogastric (NG) tube or intravenously (i.v). Twice daily (b.i.d.) administration was maintained throughout the study period. During the study, the dose of CsA was adjusted, as necessary, to achieve and maintain the C2 or C0 blood CsA concentration within the target ranges. Before enrolling the first patient, each center chose the adjunct immunosuppressive (IS) regimen between: Steroids administered and tapered as per local practice interleukin-2 receptor (IL-2R) antagonists + mycophenolic acid (MPA): Induction with IL-2R antagonists; Dosages were as per center practice. Patients received mycophenolic acid (MPA) no later than 24 hours after reperfusion of the graft. Dosages were as per local practice. The regimen selected by the center was to be given to all patients enrolled in the trial from this center.

Tacrolimus was administered within the first 24 hours post-transplantation at an initial dose of 0.1-0.15 mg/kg/day in 2 divided doses (twice daily at 12-hour interval) either orally or via a nasogastric (NG) tube or intravenously (i.v). Twice daily (b.i.d.) administration was maintained throughout study period. Throughout the study, the dose of tacrolimus was adjusted as necessary to achieve and maintain C0 tacrolimus concentrations within target ranges. Before enrolling the first patient, each center chose adjunct immunosuppressive (IS) regimen between: Steroids administered and tapered as per local practice interleukin-2 receptor (IL-2R) antagonists + mycophenolic acid (MPA): Induction with IL-2R antagonists; Dosages were as per center practice. Patients received mycophenolic acid (MPA) no later than 24 hours after reperfusion of the graft. Dosages were as per local practice. The regimen selected by center was to be given to all patients enrolled in trial from this center.

Outcomes

Primary Outcome Measures

Number of Participants With Fibrosis Score 2 or Above [Ishak-Knodell Fibrosis Score (FS) ≥ 2] Within 1 Year Post-transplant

Assessment of hepatic fibrosis was performed with liver biopsies at Day 1, Month 6, 12 and 24, read centrally by two independent pathologists blinded to treatment arm and time of biopsy. Ishak-Knodell score was used to stage liver disease; 0= None; 1= Portal fibrosis (some); 2= Portal fibrosis (most); 3= Bridging fibrosis (few); 4= Bridging fibrosis (many); 5 = Incomplete cirrhosis; 6 = Cirrhosis. Higher score indicates greater fibrosis. Logistic regression on the presence of IK>=2 was applied based on central biopsy readings only.

Secondary Outcome Measures

Number of Participants With Combined Endpoint of Death or Graft Loss or Fibrosis Score (FS) ≥ 2

The number of participants with combined end point of death or graft loss or presented with a Ishak-Knodell fibrosis score (FS) ≥2 was calculated. Graft loss was considered to have occurred when allograft was presumed to be lost if a patient had liver retransplant or died. Assessment of hepatic fibrosis was performed with liver biopsies read centrally. Ishak-Knodell FS was used to stage liver disease; 0=none; 1=portal fibrosis (some); 2=portal fibrosis (most); 3=bridging fibrosis (few); 4=bridging fibrosis (many); 5=Incomplete cirrhosis; 6=cirrhosis. Higher score indicates greater fibrosis.

Number of Participants With Fibrosing Cholestatic Hepatitis

Fibrosing cholestatic hepatitis (FCH) is characterized by progressive jaundice with a rapid decline in liver function leading to liver failure, most often associated with markedly elevated viral levels detected in the bloodstream (e.g. more than 20 times pre-liver transplantation levels) and in the liver tissue as well. The presence of FCH was reported based on the diagnosis given by the investigator.

Number of Participants With Death, Graft Loss, Death or Graft Loss, Graft Loss With Re-transplantation

Graft loss was considered to have occurred when allograft was presumed to be lost if a patient had a liver re-transplant or died.

Number of Participants With Treated Acute Rejection, Biopsy Proven Acute Rejection (BPAR), and Sub-clinical Rejection

Treated acute rejection is defined as an acute rejection, clinically suspected, whether biopsy-proven or not, which has been treated and confirmed by the investigator according to the response to therapy. BPAR was defined as a treated acute rejection confirmed by biopsy. The local pathologist graded biopsies according to the Banff (1997) criteria. A sub-clinical rejection was defined as a rejection identified by center driven biopsy, i.e. a biopsy performed routinely at some pre-defined time points after transplantation as per center practice in the absence of any clinical signs of rejection.

Number of Participants With Combined Endpoint of Death or Graft Loss or Biopsy Proven Acute Rejection (BPAR)

BPAR was defined as a treated acute rejection confirmed by biopsy. The local pathologist graded biopsies according to the Banff (1997) criteria. Graft loss was considered to have occurred when allograft was presumed to be lost if a patient had a liver re-transplant or died.

Number of Participants With Death or Re-transplantation Due to Recurrence of Hepatitis C Cirrhosis

Cirrhosis was resulted due to the recurrence of the hepatitis C virus infection in the transplanted liver.

Number of Participants With Fibrosis Score 2 or Above [Ishak-Knodell Fibrosis Score (FS) ≥ 2] Within 1 Year Post-transplant (Intent to Treat Population)

Assessment of hepatic fibrosis was performed with liver biopsies at Day 1, Month 6, 12 and 24, read centrally by two independent pathologists blinded to treatment arm and time of biopsy. Ishak-Knodell score was used to stage liver disease; 0= None; 1= Portal fibrosis (some); 2= Portal fibrosis (most); 3= Bridging fibrosis (few); 4= Bridging fibrosis (many); 5 = Incomplete cirrhosis; 6 = Cirrhosis. Higher score indicates greater fibrosis.

Mean Value of Liver Function Tests at 1 Year Post-transplantation

The mean value (in Units per liter, IU/L) of following tests were calculated at 1 year post-transplant: Serum glutamic pyruvic transaminase (SGPT) Serum Glutamic Oxaloacetic Transaminase (SGOT) Bilirubin Alkaline Phosphate γ-Glutamyltransferase (GGT)

Log-transformed Hepatitis C Virus Ribonucleic Acid (HCV RNA) Values up to 1 Year Post Transplant

HCV RNA was measured (IU/µL)centrally pre-transplant (Day 1) and at 48 hours (Day 3), Day 8 and 29, Month 6 and 12 post-transplant and concomitantly to any additional biopsies performed.

Percentage of Participants With an Increase of at Least 1 Stage in Fibrosis

Assessment of hepatic fibrosis was performed with liver biopsies at Day 1, Month 6, 12 and 24, read centrally by two independent pathologists blinded to treatment arm and time of biopsy. Ishak-Knodell score was used to stage liver disease; 0= None; 1= Portal fibrosis (some); 2= Portal fibrosis (most); 3= Bridging fibrosis (few); 4= Bridging fibrosis (many); 5 = Incomplete cirrhosis; 6 = Cirrhosis. Higher score indicates greater fibrosis. An increase of at least 1 stage demonstrated a worsening of the disease, i.e. the transition from one score to the next higher one.

Mean Fibrosis Score

Assessment of hepatic fibrosis was performed with liver biopsies at Day 1, Month 6, 12 and 24, read centrally by two independent pathologists blinded to treatment arm and time of biopsy. Ishak-Knodell score was used to stage liver disease; 0= None; 1= Portal fibrosis (some); 2= Portal fibrosis (most); 3= Bridging fibrosis (few); 4= Bridging fibrosis (many); 5 = Incomplete cirrhosis; 6 = Cirrhosis. Higher score indicates greater fibrosis. The mean score was equivalent to mean of IK at 1 and 2 years (evolution over time).

Full Information

NCT ID

NCT00260208

First Posted

November 30, 2005

Last Updated

December 2, 2011

Sponsor

Novartis Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT00260208

Brief Title

Liver Fibrosis in Patients Transplanted for Hepatitis C Receiving Either Cyclosporine Microemulsion or Tacrolimus

Official Title

A Multicenter, Randomized, Open-label Study to Compare the Development of Liver Fibrosis at 12 Months After Transplantation for Hepatitis C Cirrhosis in Patients Receiving Either Cyclosporine Microemulsion or Tacrolimus

Study Type

Interventional

2. Study Status

Record Verification Date

December 2011

Overall Recruitment Status

Terminated

Why Stopped

Study was prematurely terminated due to poor recruitment.

Study Start Date

January 2006 (undefined)

Primary Completion Date

September 2010 (Actual)

Study Completion Date

undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Pharmaceuticals

4. Oversight

5. Study Description

Brief Summary

Following a transplant for hepatitis C cirrhosis, the infection comes back in 70-90% of cases and over time causes fibrosis and eventually cirrhosis of the new liver. The aim of this study was to see if the frequency of liver fibrosis was different with cyclosporine microemulsion than tacrolimus

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Liver Transplant, Hepatitis C

Keywords

Liver transplant, adults, hepatitis C, liver fibrosis, cyclosporine microemulsion, tacrolimus

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

361 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cyclosporin A

Arm Type

Active Comparator

Arm Description

The first administration of Cyclosporin A (CsA) was within the first 24 hours post-transplantation at an initial dose of 10-15mg/kg/day either orally, via a nasogastric (NG) tube or intravenously (i.v). Twice daily (b.i.d.) administration was maintained throughout the study period. During the study, the dose of CsA was adjusted, as necessary, to achieve and maintain the C2 or C0 blood CsA concentration within the target ranges. Before enrolling the first patient, each center chose the adjunct immunosuppressive (IS) regimen between: Steroids administered and tapered as per local practice interleukin-2 receptor (IL-2R) antagonists + mycophenolic acid (MPA): Induction with IL-2R antagonists; Dosages were as per center practice. Patients received mycophenolic acid (MPA) no later than 24 hours after reperfusion of the graft. Dosages were as per local practice. The regimen selected by the center was to be given to all patients enrolled in the trial from this center.

Arm Title

Tacrolimus

Arm Type

Active Comparator

Arm Description

Tacrolimus was administered within the first 24 hours post-transplantation at an initial dose of 0.1-0.15 mg/kg/day in 2 divided doses (twice daily at 12-hour interval) either orally or via a nasogastric (NG) tube or intravenously (i.v). Twice daily (b.i.d.) administration was maintained throughout study period. Throughout the study, the dose of tacrolimus was adjusted as necessary to achieve and maintain C0 tacrolimus concentrations within target ranges. Before enrolling the first patient, each center chose adjunct immunosuppressive (IS) regimen between: Steroids administered and tapered as per local practice interleukin-2 receptor (IL-2R) antagonists + mycophenolic acid (MPA): Induction with IL-2R antagonists; Dosages were as per center practice. Patients received mycophenolic acid (MPA) no later than 24 hours after reperfusion of the graft. Dosages were as per local practice. The regimen selected by center was to be given to all patients enrolled in trial from this center.

Intervention Type

Drug

Intervention Name(s)

Cyclosporine A

Other Intervention Name(s)

Neoral

Intervention Description

Initial dose of 10-15mg/kg/day either orally, via a nasogastric (NG) tube or intravenously (i.v.) within the first 24 hours post-transplantation.

Intervention Type

Drug

Intervention Name(s)

Tacrolimus

Intervention Description

Tacrolimus was administered within the first 24 hours post-transplantation at an initial dose of 0.1-0.15 mg/kg/day in 2 divided doses either orally or via a nasogastric (NG) tube or intravenously (i.v).

Primary Outcome Measure Information:

Title

Number of Participants With Fibrosis Score 2 or Above [Ishak-Knodell Fibrosis Score (FS) ≥ 2] Within 1 Year Post-transplant

Description

Assessment of hepatic fibrosis was performed with liver biopsies at Day 1, Month 6, 12 and 24, read centrally by two independent pathologists blinded to treatment arm and time of biopsy. Ishak-Knodell score was used to stage liver disease; 0= None; 1= Portal fibrosis (some); 2= Portal fibrosis (most); 3= Bridging fibrosis (few); 4= Bridging fibrosis (many); 5 = Incomplete cirrhosis; 6 = Cirrhosis. Higher score indicates greater fibrosis. Logistic regression on the presence of IK>=2 was applied based on central biopsy readings only.

Time Frame

1 year post-transplant

Secondary Outcome Measure Information:

Title

Number of Participants With Combined Endpoint of Death or Graft Loss or Fibrosis Score (FS) ≥ 2

Description

The number of participants with combined end point of death or graft loss or presented with a Ishak-Knodell fibrosis score (FS) ≥2 was calculated. Graft loss was considered to have occurred when allograft was presumed to be lost if a patient had liver retransplant or died. Assessment of hepatic fibrosis was performed with liver biopsies read centrally. Ishak-Knodell FS was used to stage liver disease; 0=none; 1=portal fibrosis (some); 2=portal fibrosis (most); 3=bridging fibrosis (few); 4=bridging fibrosis (many); 5=Incomplete cirrhosis; 6=cirrhosis. Higher score indicates greater fibrosis.

Time Frame

1 year post-transplant

Title

Number of Participants With Fibrosing Cholestatic Hepatitis

Description

Fibrosing cholestatic hepatitis (FCH) is characterized by progressive jaundice with a rapid decline in liver function leading to liver failure, most often associated with markedly elevated viral levels detected in the bloodstream (e.g. more than 20 times pre-liver transplantation levels) and in the liver tissue as well. The presence of FCH was reported based on the diagnosis given by the investigator.

Time Frame

1 year post-transplantation

Title

Number of Participants With Death, Graft Loss, Death or Graft Loss, Graft Loss With Re-transplantation

Description

Graft loss was considered to have occurred when allograft was presumed to be lost if a patient had a liver re-transplant or died.

Time Frame

1 year post-transplant

Title

Number of Participants With Treated Acute Rejection, Biopsy Proven Acute Rejection (BPAR), and Sub-clinical Rejection

Description

Treated acute rejection is defined as an acute rejection, clinically suspected, whether biopsy-proven or not, which has been treated and confirmed by the investigator according to the response to therapy. BPAR was defined as a treated acute rejection confirmed by biopsy. The local pathologist graded biopsies according to the Banff (1997) criteria. A sub-clinical rejection was defined as a rejection identified by center driven biopsy, i.e. a biopsy performed routinely at some pre-defined time points after transplantation as per center practice in the absence of any clinical signs of rejection.

Time Frame

1 year post-transplant

Title

Number of Participants With Combined Endpoint of Death or Graft Loss or Biopsy Proven Acute Rejection (BPAR)

Description

BPAR was defined as a treated acute rejection confirmed by biopsy. The local pathologist graded biopsies according to the Banff (1997) criteria. Graft loss was considered to have occurred when allograft was presumed to be lost if a patient had a liver re-transplant or died.

Time Frame

1 year post-transplant

Title

Number of Participants With Death or Re-transplantation Due to Recurrence of Hepatitis C Cirrhosis

Description

Cirrhosis was resulted due to the recurrence of the hepatitis C virus infection in the transplanted liver.

Time Frame

1 year post-transplant

Title

Number of Participants With Fibrosis Score 2 or Above [Ishak-Knodell Fibrosis Score (FS) ≥ 2] Within 1 Year Post-transplant (Intent to Treat Population)

Description

Assessment of hepatic fibrosis was performed with liver biopsies at Day 1, Month 6, 12 and 24, read centrally by two independent pathologists blinded to treatment arm and time of biopsy. Ishak-Knodell score was used to stage liver disease; 0= None; 1= Portal fibrosis (some); 2= Portal fibrosis (most); 3= Bridging fibrosis (few); 4= Bridging fibrosis (many); 5 = Incomplete cirrhosis; 6 = Cirrhosis. Higher score indicates greater fibrosis.

Time Frame

1 year post-transplant

Title

Mean Value of Liver Function Tests at 1 Year Post-transplantation

Description

The mean value (in Units per liter, IU/L) of following tests were calculated at 1 year post-transplant: Serum glutamic pyruvic transaminase (SGPT) Serum Glutamic Oxaloacetic Transaminase (SGOT) Bilirubin Alkaline Phosphate γ-Glutamyltransferase (GGT)

Time Frame

1 year post-transplant

Title

Log-transformed Hepatitis C Virus Ribonucleic Acid (HCV RNA) Values up to 1 Year Post Transplant

Description

HCV RNA was measured (IU/µL)centrally pre-transplant (Day 1) and at 48 hours (Day 3), Day 8 and 29, Month 6 and 12 post-transplant and concomitantly to any additional biopsies performed.

Time Frame

Pre-transplant (Day 1), Day , Day 8, Day 29, Month 6 and 12 post- transplant

Title

Percentage of Participants With an Increase of at Least 1 Stage in Fibrosis

Description

Assessment of hepatic fibrosis was performed with liver biopsies at Day 1, Month 6, 12 and 24, read centrally by two independent pathologists blinded to treatment arm and time of biopsy. Ishak-Knodell score was used to stage liver disease; 0= None; 1= Portal fibrosis (some); 2= Portal fibrosis (most); 3= Bridging fibrosis (few); 4= Bridging fibrosis (many); 5 = Incomplete cirrhosis; 6 = Cirrhosis. Higher score indicates greater fibrosis. An increase of at least 1 stage demonstrated a worsening of the disease, i.e. the transition from one score to the next higher one.

Time Frame

Between 1 and 2 years

Title

Mean Fibrosis Score

Description

Assessment of hepatic fibrosis was performed with liver biopsies at Day 1, Month 6, 12 and 24, read centrally by two independent pathologists blinded to treatment arm and time of biopsy. Ishak-Knodell score was used to stage liver disease; 0= None; 1= Portal fibrosis (some); 2= Portal fibrosis (most); 3= Bridging fibrosis (few); 4= Bridging fibrosis (many); 5 = Incomplete cirrhosis; 6 = Cirrhosis. Higher score indicates greater fibrosis. The mean score was equivalent to mean of IK at 1 and 2 years (evolution over time).

Time Frame

At 1and 2 years and its evolution over time

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

No

Eligibility Criteria

Inclusion criteria Reason for transplant is end-stage liver disease due to hepatitis C cirrhosis Patients receiving a first liver transplant from a deceased or living donor Patients in whom biopsies will be possible Exclusion criteria Recipients of a liver from an hepatitis C virus positive (HCV+), human immunodeficiency virus positive (HIV+) or hepatitis B virus positive (HBV+) donor Patients with any severe coexisting disease or suffering any unstable medical condition or co-infected with HBV or HIV Patients with co-existing alcoholic disease who have not been abstinent for at least 6 months Transplanted for liver cancer exceeding a pre-defined size Pregnant or nursing women Other protocol-defined inclusion/exclusion criteria may apply

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Novartis Pharmaceuticals

Organizational Affiliation

Novartis Pharmaceuticals

Official's Role

Study Director

Facility Information:

Facility Name

Novartis Investigative Site

City

East Hanover

State/Province

New Jersey

Country

United States

Facility Name

Novartis Investigational Site

City

Zurich

ZIP/Postal Code

8091

Country

Switzerland

Liver Transplant, Hepatitis C

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial