Ignite Creation Date:
2024-05-05 @ 12:01 PM
Last Modification Date:
2024-10-26 @ 9:18 AM
Study NCT ID:
NCT00211848
Status:
COMPLETED
Last Update Posted:
2017-01-27
First Post:
2005-09-13
Brief Title:
Antiviral Antifibrotic Liver Therapy in HCV Drinkers and Non-Drinkers
Sponsor:
Icahn School of Medicine at Mount Sinai
Organization:
Icahn School of Medicine at Mount Sinai
Study Overview
Official Title:
Antiviral Antifibrotic Liver Therapy in HCV Drinkers and Non-Drinkers
Status:
COMPLETED
Status Verified Date:
2007-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The primary aim of this investigation is to evaluate the effect of a combined antiviral antifibrotic and antioxidant treatment on the progression of liver disease in patients with hepatitis C who either abstain from alcohol or continue to drink All subjects are given state-of-the-art antiviral treatment pegylated interferon ribavirin supplemented with either placebo or polyenylphosphatidylcholine PPC a purified soybean extract consisting of 95-96 polyunsaturated phosphatidylcholines PC and which has both antifibrotic and antioxidant properties Secondary aims are to verify whether moderate alcohol consumption interferes with the antiviral effect of pegylated interferon ribavirin on HCV and to validate the reliability of various circulating markers as substitute for liver biopsies to indicate the stage of liver pathology and its propensity for progression
Detailed Description:
Current therapy for HCV disease focuses on anti-viral treatment The combination of pegylated interferon and ribavirin is approved by the FDA for treating HCV disease Subjects in this study will be given ribavirin and pegylated interferon One innovative aspect of this proposal is that the state-of-the-art antiviral treatment will be supplemented by an anti-fibrotic agent namely polyenylphosphatidylcholine PPC or placebo administered in a double blind randomized fashion Current therapy focuses on anti-viral treatment neglecting the fact that what causes the medical symptoms and eventually the demise of the HCV patient is the liver fibrosis the resulting cirrhosis and the associated complications including hepatocellular carcinoma If the fibrotic process could be stopped or even prevented the hepatitis C virus would lose much of its impact on health Available anti-fibrotic agents are too toxic to be used in patients except for one namely PPC which has been shown in various experimental models to have striking anti-fibrotic actions and was found recently in a European study to be beneficial in patients with hepatitis C in terms of their circulating levels of transaminases Various studies have indicated that HCV is associated with an oxidative stress and thus it is noteworthy that PPC was discovered to have also significant anti-oxidant effects
The study has been approved by the Institutional Review Board at each Center and all the patients are provided written informed consent After screening patients are randomly assigned to one of 2 treatment groups PPC or placebo The two treatment groups are given the combination of pegylated interferon 180 μg injected once weekly Shiffman et al 1999 Sulkowski et al 1999 and ribavirin for 48 weeks genotype I or 24 weeks other genotypes If the latter do not respond in terms of HCV RNA they are also treated for 48 weeks Ribavirin is administered orally twice a day at a total daily dose of 1000 mg for patients who weigh 75 kg or less and 1200 mg for those who weigh more than 75 kg These drugs are started and stopped at the same time the PPC 5 chewable tablets of 09 gm each per day or corresponding placebo obtained from PHOSPHOLIPID GmbH a successor of Rhone-Poulenc Rorer Cologne Germany are given to each patient for the 3 years
The patients in whom the hemoglobin falls by more than 2 g per deciliter are followed every 2 weeks until stabilization The dose of ribavirin is reduced to 600 mg per day in patients whose hemoglobin concentrations fall below 10 g per deciliter and it is discontinued if the concentration falls below 85 g per deciliter For severe adverse events other than anemia the dose of interferon is reduced in half and the dose of ribavirin to 600 mg per day The full dose can be resumed after the event or discontinued if the effect persists
The patients are evaluated as outpatients at weeks 1 2 4 and then every 4 weeks during the 24-48 weeks of interferon-ribavirin-PPC or placebo treatment as well as during the subsequent PPC placebo therapy Upon cessation of antiviral treatment study patients may be seen on a quarterly basis if in the Investigators judgment this flexible schedule will not impact negatively on patient care but will impact positively on patient retention Biochemical testing is performed by a central laboratory Plasma HCV RNA levels are determined before treatment during interferon-ribavirin treatment at 24 and 48 weeks after interferon-ribavirin therapy at months 18 24 and 30 and at the end of the 3 years Plasma HCV RNA is measured by a quantitative reverse-transcription-polymerase-chain-reaction assay Cobas Amplicor for HCV Monitor v2 Roche Diagnostic Systems Inc that has a sensitivity of 3000 IUml with a linearity up to 25 X 106 IUml Samples negative with the quantitative HCV-RNA are retested with the qualitative HCV-PCR assay Cobas Amplicor for HCV 20 Roche Diagnostic Systems Inc that has a sensitivity of 60 IUml HCV genotyping is carried out according to Stuyver et al 1993 Inno-LIPA HCVII Immunogenetics
Compliance in terms of PPC or placebo will be monitored by 4 methods patient diary pill count of the medication and monthly urine analysis for the presence of a riboflavin marker Patients will consume 60 mg riboflavin per day Riboflavin is rapidly excreted in the urine and is fluorescent when passed under an ultraviolet lamp In addition spot checks of blood levels of dilinoleoylphosphatidylcholine DLPC the main phosphatidylcholine species of PPC will validate compliance
Alcohol intake will be monitored by 3 methods patient diary collateral history and monthly blood tests for markers of alcohol consumption carbohydrate deficient transferrinCDT
Liver biopsies are performed at the end of 3 years and the specimens analyzed by two pathologists who are unaware of the patients identification and treatment regimen Fibrosis is the major criterion with some assessment in additional areas such as virologic response examined in both drinkers and non-drinkers
1 Fibrosis The primary statistical analysis will compare the PPC and placebo groups with regard to changes in fibrosis score from baseline to the value after 36 months of treatment The primary fibrosis end point is histological with degrees of fibrosis graded on liver biopsy according to Ishak et al 1995 Furthermore we count the number of α-smooth muscle actin SMA expressing stellate cells Reeves et al 1996 the principal collagen producing cells Activation of stellate cells and their transformation to myofibroblast-like cells has been demonstrated in experimental fibrosis Mak et al 1984 1994 Smooth muscle actin α is an actin isoform typical of smooth muscle cells Skalli et al 1986 that may be localized in stellate cells of the human liver Its expression in the stellate cells has been considered an indication of phenotypic modulation of stellate cells to myofibroblasts In the human liver the appearance of smooth muscle actin α was closely related to the process of hepatic fibrosis Reeves et al 1996 and the formation of cirrhotic nodules Nouchi et al 1991 In addition circulating break-down products of collagen or other components of the extracellular matrix ECM are being used as markers of liver pathology These include laminin the major noncollagenous glycoprotein of basement membranes Indeed extracellular basement membranes undergo a continuous turnover and elevation of laminin has been described in the sera of patients with alcoholic liver disease Niemelä et al 1988 Sato et al 1986 Tenascin a molecule expressed in proliferating ECM TIMP-1 an inhibitor of the matrix degrading metalloproteinases MMPs collagen IV collagen VI a molecule that forms filaments between large collagen fibrils the N-terminal propeptide of procollagen type III PIIINP considered a marker of fibrogenesis hyaluronic acid HA an ubiquitous glycosaminoglycan with high extraction by the liver sinusoidal endothelium and MMP-2 All these have been assessed before as markers of fibrosis some specifically in patients with chronic hepatitis C Kasahara et al 1997 McHutchison et al 2000 Kojima et la 2001 Murawaki et al 2001 but not in subjects who were also drinkers
2 Sustained virologic response defined as the absence of plasma HCV RNA a minimum of 24 weeks after antiviral treatment is completed
The study has been approved by the Institutional Review Board at each Center and all the patients are provided written informed consent After screening patients are randomly assigned to one of 2 treatment groups PPC or placebo The two treatment groups are given the combination of pegylated interferon 180 μg injected once weekly Shiffman et al 1999 Sulkowski et al 1999 and ribavirin for 48 weeks genotype I or 24 weeks other genotypes If the latter do not respond in terms of HCV RNA they are also treated for 48 weeks Ribavirin is administered orally twice a day at a total daily dose of 1000 mg for patients who weigh 75 kg or less and 1200 mg for those who weigh more than 75 kg These drugs are started and stopped at the same time the PPC 5 chewable tablets of 09 gm each per day or corresponding placebo obtained from PHOSPHOLIPID GmbH a successor of Rhone-Poulenc Rorer Cologne Germany are given to each patient for the 3 years
The patients in whom the hemoglobin falls by more than 2 g per deciliter are followed every 2 weeks until stabilization The dose of ribavirin is reduced to 600 mg per day in patients whose hemoglobin concentrations fall below 10 g per deciliter and it is discontinued if the concentration falls below 85 g per deciliter For severe adverse events other than anemia the dose of interferon is reduced in half and the dose of ribavirin to 600 mg per day The full dose can be resumed after the event or discontinued if the effect persists
The patients are evaluated as outpatients at weeks 1 2 4 and then every 4 weeks during the 24-48 weeks of interferon-ribavirin-PPC or placebo treatment as well as during the subsequent PPC placebo therapy Upon cessation of antiviral treatment study patients may be seen on a quarterly basis if in the Investigators judgment this flexible schedule will not impact negatively on patient care but will impact positively on patient retention Biochemical testing is performed by a central laboratory Plasma HCV RNA levels are determined before treatment during interferon-ribavirin treatment at 24 and 48 weeks after interferon-ribavirin therapy at months 18 24 and 30 and at the end of the 3 years Plasma HCV RNA is measured by a quantitative reverse-transcription-polymerase-chain-reaction assay Cobas Amplicor for HCV Monitor v2 Roche Diagnostic Systems Inc that has a sensitivity of 3000 IUml with a linearity up to 25 X 106 IUml Samples negative with the quantitative HCV-RNA are retested with the qualitative HCV-PCR assay Cobas Amplicor for HCV 20 Roche Diagnostic Systems Inc that has a sensitivity of 60 IUml HCV genotyping is carried out according to Stuyver et al 1993 Inno-LIPA HCVII Immunogenetics
Compliance in terms of PPC or placebo will be monitored by 4 methods patient diary pill count of the medication and monthly urine analysis for the presence of a riboflavin marker Patients will consume 60 mg riboflavin per day Riboflavin is rapidly excreted in the urine and is fluorescent when passed under an ultraviolet lamp In addition spot checks of blood levels of dilinoleoylphosphatidylcholine DLPC the main phosphatidylcholine species of PPC will validate compliance
Alcohol intake will be monitored by 3 methods patient diary collateral history and monthly blood tests for markers of alcohol consumption carbohydrate deficient transferrinCDT
Liver biopsies are performed at the end of 3 years and the specimens analyzed by two pathologists who are unaware of the patients identification and treatment regimen Fibrosis is the major criterion with some assessment in additional areas such as virologic response examined in both drinkers and non-drinkers
1 Fibrosis The primary statistical analysis will compare the PPC and placebo groups with regard to changes in fibrosis score from baseline to the value after 36 months of treatment The primary fibrosis end point is histological with degrees of fibrosis graded on liver biopsy according to Ishak et al 1995 Furthermore we count the number of α-smooth muscle actin SMA expressing stellate cells Reeves et al 1996 the principal collagen producing cells Activation of stellate cells and their transformation to myofibroblast-like cells has been demonstrated in experimental fibrosis Mak et al 1984 1994 Smooth muscle actin α is an actin isoform typical of smooth muscle cells Skalli et al 1986 that may be localized in stellate cells of the human liver Its expression in the stellate cells has been considered an indication of phenotypic modulation of stellate cells to myofibroblasts In the human liver the appearance of smooth muscle actin α was closely related to the process of hepatic fibrosis Reeves et al 1996 and the formation of cirrhotic nodules Nouchi et al 1991 In addition circulating break-down products of collagen or other components of the extracellular matrix ECM are being used as markers of liver pathology These include laminin the major noncollagenous glycoprotein of basement membranes Indeed extracellular basement membranes undergo a continuous turnover and elevation of laminin has been described in the sera of patients with alcoholic liver disease Niemelä et al 1988 Sato et al 1986 Tenascin a molecule expressed in proliferating ECM TIMP-1 an inhibitor of the matrix degrading metalloproteinases MMPs collagen IV collagen VI a molecule that forms filaments between large collagen fibrils the N-terminal propeptide of procollagen type III PIIINP considered a marker of fibrogenesis hyaluronic acid HA an ubiquitous glycosaminoglycan with high extraction by the liver sinusoidal endothelium and MMP-2 All these have been assessed before as markers of fibrosis some specifically in patients with chronic hepatitis C Kasahara et al 1997 McHutchison et al 2000 Kojima et la 2001 Murawaki et al 2001 but not in subjects who were also drinkers
2 Sustained virologic response defined as the absence of plasma HCV RNA a minimum of 24 weeks after antiviral treatment is completed
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 99-1097 | None | None | None |