Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00180674 |
| Other study ID # |
aclf01 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
August 2005 |
| Est. completion date |
October 2006 |
Study information
| Verified date |
November 2020 |
| Source |
Imperial College London |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
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. Mary's 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 iu/ml, 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 units/week); 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 hospital's
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 patient's participation in the study.
