Ignite Creation Date:
2024-05-05 @ 11:56 AM
Last Modification Date:
2024-10-26 @ 9:16 AM
Study NCT ID:
NCT00180674
Status:
COMPLETED
Last Update Posted:
2020-12-01
First Post:
2005-09-13
Brief Title:
Anticoagulation in Liver Fibrosis in Patients With Hepatitis C Virus Infection
Sponsor:
Imperial College London
Organization:
Imperial College London
Study Overview
Official Title:
Anticoagulation for Liver Fibrosis in Patients With Hepatitis C Virus Infection Pilot Study
Status:
COMPLETED
Status Verified Date:
2020-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Patients who have been treated for hepatitis C virus HCV infection who have failed to respond to anti-viral treatment are often concerned about their ongoing liver disease and are therefore looking for alternative treatments which might prevent fibrosis progression This view is endorsed by patient representative groups including Charles Gore at the HepC Trust who have welcomed this trial protocol
The study is a single centred prospective open labelled design Practical as well as safety concerns dictated that the study could not be conducted in a blinded fashion since patients taking anticoagulation require monitoring The study consisted of two 8 week phases Phase 1 and Phase 2 Phase 1 observation phase 0 to 8 weeks and Phase 2 treatment phase with warfarin anticoagulation 8 to 16 weeks Study completed at end of Phase 2
The study is a single centred prospective open labelled design Practical as well as safety concerns dictated that the study could not be conducted in a blinded fashion since patients taking anticoagulation require monitoring The study consisted of two 8 week phases Phase 1 and Phase 2 Phase 1 observation phase 0 to 8 weeks and Phase 2 treatment phase with warfarin anticoagulation 8 to 16 weeks Study completed at end of Phase 2
Detailed Description:
Background
Convincing evidence exists outlining a role for the coagulation system in the pathogenesis of liver fibrosis In vivo and in vitro studies have suggested a role for thrombin and FXa in activating hepatic stellate cells and epidemiological studies have demonstrated that prothrombotic states accelerate liver fibrosis Wright et al 2003
Hence if prothrombotic states accelerate liver fibrosis conversely anticoagulation should slow liver fibrosis Animal studies have confirmed this Anstee et al 2008 Duplantier et al 2004 and confirmed the beneficial effect of inhibiting the coagulation cascade The number of patients with HCV infection on anticoagulants is small and there is no published case series Similarly there are problems assessing disease progression using patients with haemophilia and HCV infection The therapeutic use of anticoagulation to prevent fibrosis in humans is not without precedent and warfarin has demonstrated a survival benefit in pulmonary fibrosis Kubo et al 2005
The antifibrotic potential of warfarin anticoagulation needs to be formally assessed in the setting of a clinical trial using patients with documented liver fibrosis Most previous human studies of antifibrotics have taken place in patients with chronic HCV infection who have failed anti-viral therapy as they are a model of progressive fibrosis Anstee et al 2009
Study aims
1 To evaluate if any potential effect on the progression of liver fibrosis in patients infected with Hepatitis C virus with moderate severity liver fibrosis is demonstrable with anticoagulation
2 To evaluate the safety of anticoagulation in patients infected with Hepatitis C virus infection with moderate severity liver fibrosis
Patients
The study was approved by the St Marys Hospital Ethics committee and conducted in accordance with the principles of the Declaration of Helsinki Potential participants were identified via the departmental Hepatitis C database All potential candidates were screened for the inclusion and exclusion criteria
Inclusion criteria
Patients were eligible for inclusion if they were aged greater than 17 years of age had evidence of active Hepatitis C viral replication HCV RNA PCR positive ALT of greater than 40 iuml a modified histology activity index fibrosis score Ishak et al 1995 of greater than 2 but less than 5 on liver biopsy within the last five years and had failed antiviral therapy for Hepatitis C in the last 5 years
Exclusion criteria
Patients requiring anticoagulation for existing clinical indications standard contraindications to anticoagulation active peptic ulcer disease past history of haemorrhagic stroke thrombocytopaenia platelets count 100 x109 L clinical evidence of portal hypertension known cerebrovascular abnormalities HIV antibody positive alcohol abuse 40 unitsweek menhorragia and pregnancy
Potential qualifying subjects were initially contacted by telephone to be informed about the study and arrange a formal screening visit During the screening visit entry criteria were confirmed and all patients who agreed to participate were required to give written informed consent
Study design
The study employed a single centred prospective open labelled design Practical as well as safety concerns dictated that the study could not be conducted in a blinded fashion since patients taking anticoagulation require monitoring The study consisted of two 8 week phases Phase 1 and Phase 2
Phase 1 Week 0 to Week 8 Phase 1 of the study consisted of 8 weeks of observation which commenced following a baseline visit at week 0 At the baseline study routine blood tests and non-invasive markers of fibrosis were performed No placebo was given during the observation period At week 8 patients underwent their second study visit during which routine blood tests and evaluation with non-invasive markers of fibrosis were repeated The week 8 study visit marked the completion of Phase 1 following which patients entered Phase 2 of the study
Phase 2 Week 8 to Week 16 Phase 2 of the study consisted of 8 weeks of anticoagulation with warfarin In previous animal studies Anstee et al 2008 warfarin anticoagulation to achieve a whole blood clotting of twice the normal range was sufficient to retard fibrosis significantly hence the international normalised ration INR was aimed to be maintained between 2 to 3 during the treatment period Patients were given a standard induction regimen of warfarin in keeping with the outpatient warfarin loading protocol of the hospitals anticoagulation clinic Warfarin was supplied by the hospital pharmacy Routine INR monitoring and warfarin dosing was undertaken by the anticoagulation clinic on a weekly basis Patients were monitored at these visits for any adverse events related to the treatment At week 16 following 8 weeks of anticoagulation a further study visit was organised Routine bloods tests and non-invasive markers of fibrosis were performed at this visit which marked the completion of each patients participation in the study
Convincing evidence exists outlining a role for the coagulation system in the pathogenesis of liver fibrosis In vivo and in vitro studies have suggested a role for thrombin and FXa in activating hepatic stellate cells and epidemiological studies have demonstrated that prothrombotic states accelerate liver fibrosis Wright et al 2003
Hence if prothrombotic states accelerate liver fibrosis conversely anticoagulation should slow liver fibrosis Animal studies have confirmed this Anstee et al 2008 Duplantier et al 2004 and confirmed the beneficial effect of inhibiting the coagulation cascade The number of patients with HCV infection on anticoagulants is small and there is no published case series Similarly there are problems assessing disease progression using patients with haemophilia and HCV infection The therapeutic use of anticoagulation to prevent fibrosis in humans is not without precedent and warfarin has demonstrated a survival benefit in pulmonary fibrosis Kubo et al 2005
The antifibrotic potential of warfarin anticoagulation needs to be formally assessed in the setting of a clinical trial using patients with documented liver fibrosis Most previous human studies of antifibrotics have taken place in patients with chronic HCV infection who have failed anti-viral therapy as they are a model of progressive fibrosis Anstee et al 2009
Study aims
1 To evaluate if any potential effect on the progression of liver fibrosis in patients infected with Hepatitis C virus with moderate severity liver fibrosis is demonstrable with anticoagulation
2 To evaluate the safety of anticoagulation in patients infected with Hepatitis C virus infection with moderate severity liver fibrosis
Patients
The study was approved by the St Marys Hospital Ethics committee and conducted in accordance with the principles of the Declaration of Helsinki Potential participants were identified via the departmental Hepatitis C database All potential candidates were screened for the inclusion and exclusion criteria
Inclusion criteria
Patients were eligible for inclusion if they were aged greater than 17 years of age had evidence of active Hepatitis C viral replication HCV RNA PCR positive ALT of greater than 40 iuml a modified histology activity index fibrosis score Ishak et al 1995 of greater than 2 but less than 5 on liver biopsy within the last five years and had failed antiviral therapy for Hepatitis C in the last 5 years
Exclusion criteria
Patients requiring anticoagulation for existing clinical indications standard contraindications to anticoagulation active peptic ulcer disease past history of haemorrhagic stroke thrombocytopaenia platelets count 100 x109 L clinical evidence of portal hypertension known cerebrovascular abnormalities HIV antibody positive alcohol abuse 40 unitsweek menhorragia and pregnancy
Potential qualifying subjects were initially contacted by telephone to be informed about the study and arrange a formal screening visit During the screening visit entry criteria were confirmed and all patients who agreed to participate were required to give written informed consent
Study design
The study employed a single centred prospective open labelled design Practical as well as safety concerns dictated that the study could not be conducted in a blinded fashion since patients taking anticoagulation require monitoring The study consisted of two 8 week phases Phase 1 and Phase 2
Phase 1 Week 0 to Week 8 Phase 1 of the study consisted of 8 weeks of observation which commenced following a baseline visit at week 0 At the baseline study routine blood tests and non-invasive markers of fibrosis were performed No placebo was given during the observation period At week 8 patients underwent their second study visit during which routine blood tests and evaluation with non-invasive markers of fibrosis were repeated The week 8 study visit marked the completion of Phase 1 following which patients entered Phase 2 of the study
Phase 2 Week 8 to Week 16 Phase 2 of the study consisted of 8 weeks of anticoagulation with warfarin In previous animal studies Anstee et al 2008 warfarin anticoagulation to achieve a whole blood clotting of twice the normal range was sufficient to retard fibrosis significantly hence the international normalised ration INR was aimed to be maintained between 2 to 3 during the treatment period Patients were given a standard induction regimen of warfarin in keeping with the outpatient warfarin loading protocol of the hospitals anticoagulation clinic Warfarin was supplied by the hospital pharmacy Routine INR monitoring and warfarin dosing was undertaken by the anticoagulation clinic on a weekly basis Patients were monitored at these visits for any adverse events related to the treatment At week 16 following 8 weeks of anticoagulation a further study visit was organised Routine bloods tests and non-invasive markers of fibrosis were performed at this visit which marked the completion of each patients participation in the study
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None