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Sustained Virological Response (SVR) to Antiviral Treatment of Liver Transplant Recipients With Recurrent Hepatitis C (SUSTAIN)

Primary Purpose

Hepatitis C, Liver Transplantation

Status
Completed
Phase
Phase 4
Locations
International
Study Type
Interventional
Intervention
cyclosporin (Neoral)
tacrolimus (Prograf)
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hepatitis C focused on measuring Hepatitis C, liver transplantation, anti-viral therapy

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Neoral

tacrolimus

Arm Description

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.

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

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
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)
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)
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)
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)
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)
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)
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

Full Information

First Posted
July 13, 2009
Last Updated
May 5, 2015
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT00938860
Brief Title
Sustained Virological Response (SVR) to Antiviral Treatment of Liver Transplant Recipients With Recurrent Hepatitis C
Acronym
SUSTAIN
Official Title
A Multi-center, Randomized, Open Label, Controlled Study to Compare the Sustained Virological Response During Treatment With Neoral or Tacrolimus in Maintenance Liver Transplant Recipients Treated With Pegylated Interferon and Ribavirin for Recurrent Hepatitis C
Study Type
Interventional

2. Study Status

Record Verification Date
May 2015
Overall Recruitment Status
Completed
Study Start Date
September 2009 (undefined)
Primary Completion Date
May 2013 (Actual)
Study Completion Date
May 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatitis C, Liver Transplantation
Keywords
Hepatitis C, liver transplantation, anti-viral therapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
92 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Neoral
Arm Type
Experimental
Arm Description
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
Arm Title
tacrolimus
Arm Type
Active Comparator
Arm Description
Tacrolimus capsules bid, doses were adjusted as necessary to achieve and maintain recommended C0 target ranges.
Intervention Type
Drug
Intervention Name(s)
cyclosporin (Neoral)
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
tacrolimus (Prograf)
Intervention Description
Tacrolimus capsules bid, doses were adjusted as necessary to achieve and maintain recommended C0 target ranges.
Primary Outcome Measure Information:
Title
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
Description
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
Secondary Outcome Measure Information:
Title
Number of Events of the Composite Endpoint of Biopsy Proven Acute Rejections (BPAR), Death or Graft Loss and of the Individual Components
Description
Efficacy failure (biopsy proven acute rejection (BPAR), graft loss, or death
Time Frame
Week 80
Title
Number of Participants With Fibrosis Progression (Increase in Ishak-Knodell (IK) Score by at Least One Point From the Baseline)
Description
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
Title
Number of Participants of Rapid Viral Response (RVR)
Description
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
Title
Number of Participants of Early Viral Response (EVR)
Description
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
Title
Number of Participants for the End of Treatment Response (ETR)
Description
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
Title
Number of Participants of True Non-responder Rate
Description
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
Title
Number of Participants for Relapse Rate
Description
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
Title
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
Description
Defined as number of patients with dose reduction or discontinuation of AV therapy due to poor tolerability
Time Frame
Week 80

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
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
Phoenix
State/Province
Arizona
ZIP/Postal Code
85054
Country
United States
Facility Name
Novartis Investigative Site
City
Palo Alto
State/Province
California
ZIP/Postal Code
95128
Country
United States
Facility Name
Novartis Investigative Site
City
San Francisco
State/Province
California
ZIP/Postal Code
94143-2205
Country
United States
Facility Name
Novartis Investigative Site
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610
Country
United States
Facility Name
Novartis Investigative Site
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599-7211
Country
United States
Facility Name
Novartis Investigative Site
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73112
Country
United States
Facility Name
Novartis Investigative Site
City
Houston
State/Province
Texas
ZIP/Postal Code
77030-2400
Country
United States
Facility Name
Novartis Investigative Site
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
Novartis Investigative Site
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53792
Country
United States
Facility Name
Novartis Investigative Site
City
Bruxelles
ZIP/Postal Code
1070
Country
Belgium
Facility Name
Novartis Investigative Site
City
Fortaleza
State/Province
CE
ZIP/Postal Code
60430-270
Country
Brazil
Facility Name
Novartis Investigative Site
City
São Paulo
State/Province
SP
ZIP/Postal Code
04023-900
Country
Brazil
Facility Name
Novartis Investigative Site
City
Edmonton
State/Province
Alberta
ZIP/Postal Code
T6G 2B7
Country
Canada
Facility Name
Novartis Investigative Site
City
Vancouver
State/Province
British Columbia
ZIP/Postal Code
V5Z 1M9
Country
Canada
Facility Name
Novartis Investigative Site
City
Winnipeg
State/Province
Manitoba
ZIP/Postal Code
R3E 0W3
Country
Canada
Facility Name
Novartis Investigative Site
City
London
State/Province
Ontario
ZIP/Postal Code
N6A 4G5
Country
Canada
Facility Name
Novartis Investigative Site
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2C4
Country
Canada
Facility Name
Novartis Investigative Site
City
Bogotá
State/Province
Cundinamarca
ZIP/Postal Code
110111
Country
Colombia
Facility Name
Novartis Investigative Site
City
Bogotá
Country
Colombia
Facility Name
Novartis Investigative Site
City
Creteil
ZIP/Postal Code
94000
Country
France
Facility Name
Novartis Investigative Site
City
Lyon Cedex 04
ZIP/Postal Code
69317
Country
France
Facility Name
Novartis Investigative Site
City
Montpellier
ZIP/Postal Code
34295
Country
France
Facility Name
Novartis Investigative Site
City
Paris
ZIP/Postal Code
75012
Country
France
Facility Name
Novartis Investigative Site
City
Toulouse Cedex 4
ZIP/Postal Code
31054
Country
France
Facility Name
Novartis Investigative Site
City
Villejuif
ZIP/Postal Code
94800
Country
France
Facility Name
Novartis Investigative Site
City
Frankfurt
ZIP/Postal Code
60590
Country
Germany
Facility Name
Novartis Investigative Site
City
Hamburg
ZIP/Postal Code
20246
Country
Germany
Facility Name
Novartis Investigative Site
City
Mainz
ZIP/Postal Code
55131
Country
Germany
Facility Name
Novartis Investigative Site
City
Muenchen
ZIP/Postal Code
81377
Country
Germany
Facility Name
Novartis Investigative Site
City
Bologna
State/Province
BO
ZIP/Postal Code
40138
Country
Italy
Facility Name
Novartis Investigative Site
City
Padova
State/Province
PD
ZIP/Postal Code
35128
Country
Italy
Facility Name
Novartis Investigative Site
City
Udine
State/Province
UD
ZIP/Postal Code
33100
Country
Italy
Facility Name
Novartis Investigative Site
City
Seoul
State/Province
Korea
ZIP/Postal Code
110 744
Country
Korea, Republic of
Facility Name
Novartis Investigative Site
City
Seoul
State/Province
Korea
ZIP/Postal Code
120-752
Country
Korea, Republic of
Facility Name
Novartis Investigative Site
City
Seoul
State/Province
Korea
ZIP/Postal Code
135-710
Country
Korea, Republic of
Facility Name
Novartis Investigative Site
City
Seoul
State/Province
Korea
ZIP/Postal Code
137-701
Country
Korea, Republic of
Facility Name
Novartis Investigative Site
City
Moscow
ZIP/Postal Code
123182
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
Moscow
ZIP/Postal Code
129010
Country
Russian Federation
Facility Name
Novartis Investigative Site
City
Oviedo
State/Province
Asturias
ZIP/Postal Code
33006
Country
Spain
Facility Name
Novartis Investigative Site
City
Valladolid
State/Province
Castilla y Leon
ZIP/Postal Code
47012
Country
Spain
Facility Name
Novartis Investigative Site
City
Barcelona
State/Province
Catalunya
ZIP/Postal Code
08035
Country
Spain
Facility Name
Novartis Investigative Site
City
Barcelona
State/Province
Catalunya
ZIP/Postal Code
08036
Country
Spain
Facility Name
Novartis Investigative Site
City
Santiago de Compostela
State/Province
Galicia
ZIP/Postal Code
15706
Country
Spain
Facility Name
Novartis Investigative Site
City
Zurich
ZIP/Postal Code
8091
Country
Switzerland
Facility Name
Novartis Investigative Site
City
Birmingham
ZIP/Postal Code
B15 2TT
Country
United Kingdom

12. IPD Sharing Statement

Learn more about this trial

Sustained Virological Response (SVR) to Antiviral Treatment of Liver Transplant Recipients With Recurrent Hepatitis C

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