Anticoagulation in Liver Fibrosis in Patients With Hepatitis C Virus Infection

• Sponsor: Imperial College London (Other)
• Overall Status: Completed
• CT.gov ID: NCT00180674
• Collaborator: (none)
• Enrollment: 14
• Location: 1
• Arm: 1
• Duration (Months): 14
• Patients Per Site Per Month: 1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Liver Fibrosis	Drug: Warfarin	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. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: 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.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.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Anticoagulation for Liver Fibrosis in Patients With Hepatitis C Virus Infection: Pilot Study
• Study Start Date: Aug 1, 2005
• Actual Primary Completion Date: Sep 1, 2006
• Actual Study Completion Date: Oct 1, 2006

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Warfarin anticoagulation Anticoagulated with warfarin to maintain an INR of 2-3 between 8 and 16 weeks (treatment period).	Drug: Warfarin

Outcome Measures

Primary Outcome Measures

1. Median Liver Stiffness Value [Baseline (start of the observation period at week 0), 8-weeks (completion of the observation period) and 16-weeks (completion of the period of anticoagulation)]

   Median liver stiffness at 16-weeks following the 8-week period of anticoagulation, compared to 8-week period of observation. kPa values reported are the values from completion of the period of anticoagulation at week 16 versus completion of the observation period at week 8, and start of the observation period at week 0.

Secondary Outcome Measures

1. Number of Participants With Adverse Events [8-week period of warfarin treatment and 8-week observation period (16 weeks)]

   The secondary endpoints were the proportion of patients with a reduction in serum markers of fibrosis and HTTs following the 8-week period of anticoagulation compared to the 8-week period of observation and the safety of anticoagulation defined by the number of adverse events.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 17 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Aged >17 years (male and female)

• HCV infection PCR positive

• ALT > 40 iu/ml

• Ishak fibrosis score (within last 5 years) > 2, < 5

• Informed consent

• Failed antiviral therapy for HCV in last 5 years

Exclusion Criteria:

• Patients requiring anticoagulation for existing clinical indications

• Active peptic ulcer disease

• Past history of haemorrhagic stroke

• Thrombocytopaenia (platelets count < 100 x 109 /L)

• Clinical evidence of portal hypertension

• Known cerebrovascular abnormalities;

• HIV antibody positive;

• Alcohol abuse (>40 unites/week)

• Menhorragia

• Pregnancy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	St Mary's Hospital NHS Trust	London		United Kingdom	W2 1NY

Sponsors and Collaborators

• Imperial College London

Investigators

• Principal Investigator: Mark R Thursz, MBBS, FRCP, St Mary's Hospital & Imperial College London

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Result publication

Publications

None provided.

• Responsible Party: Imperial College London
• ClinicalTrials.gov Identifier: NCT00180674
• Other Study ID Numbers: aclf01
• First Posted: Sep 16, 2005
• Last Update Posted: Dec 1, 2020
• Last Verified: Nov 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Imperial College London: Hepatic fibrosis; anticoagulation; Coumarin; Warfarin; Chronic hepatitis C virus infection
• Additional relevant MeSH terms: Infections; Hepatitis C; Virus Diseases; Hepatitis; Liver Cirrhosis; Fibrosis; Warfarin

Study Results

Participant Flow

Pre-assignment Detail	A total of 14 patients were enrolled in the study. Ten patients completed the study. Four patients withdrew from the study, all during the Phase 1 Observation Period due to personal reasons. These 4 patients did not participate in Phase 2, Treatment Period and they are not included in the analyses.

Arm/Group Title	Warfarin Anticoagulation
Arm/Group Description	Anticoagulated with warfarin to maintain an INR of 2-3 between 8 and 16 weeks (Phase 2, Treatment Period).
Period Title: Phase 1, Observation Period
STARTED	14
COMPLETED	10
NOT COMPLETED	4
Period Title: Phase 1, Observation Period
STARTED	10
COMPLETED	9
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Warfarin Anticoagulation
Arm/Group Description	Anticoagulated with warfarin to maintain an INR of 2-3 between 8 and 16 weeks (Phase 2, Treatment Period).
Overall Participants	10
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	10 100%
>=65 years	0 0%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	49.5
Sex: Female, Male (Count of Participants)
Female	4 40%
Male	6 60%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (participants) [Number]
United Kingdom	10 100%

Outcome Measures

1. Primary Outcome

Title	Median Liver Stiffness Value
Description	Median liver stiffness at 16-weeks following the 8-week period of anticoagulation, compared to 8-week period of observation. kPa values reported are the values from completion of the period of anticoagulation at week 16 versus completion of the observation period at week 8, and start of the observation period at week 0.
Time Frame	Baseline (start of the observation period at week 0), 8-weeks (completion of the observation period) and 16-weeks (completion of the period of anticoagulation)

Outcome Measure Data

Analysis Population Description

One participant excluded from Phase 2, Warfarin Anticoagulation Period due to a non serious adverse event.

Arm/Group Title	Observation Period	Warfarin Anticoagulation
Arm/Group Description	Phase 1, Observation Period Observation period began at Week 0 and was completed at Week 8.	Phase 2, Treatment Period Anticoagulated with warfarin to maintain an INR of 2-3 between 8 and 16 weeks (treatment period).
Measure Participants	10	9
Median (Inter-Quartile Range) [kPa]	7.70	6.90

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Period
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.043
	Comments
	Method	Wilcoxon Signed Ranks test
	Comments

2. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	The secondary endpoints were the proportion of patients with a reduction in serum markers of fibrosis and HTTs following the 8-week period of anticoagulation compared to the 8-week period of observation and the safety of anticoagulation defined by the number of adverse events.
Time Frame	8-week period of warfarin treatment and 8-week observation period (16 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Observation Period	Warfarin Treatment Period
Arm/Group Description	Phase 1, Observation Period Phase 1 of the study consisted of 8 weeks of observation, which commenced following a baseline visit at week 0.	Phase 2, Treatment Period: Anticoagulated with warfarin to maintain an INR of 2-3 between 8 and 16 weeks (treatment period).
Measure Participants	10	9
Count of Participants [Participants]	0 0%	1 NaN

Adverse Events

Time Frame	16 weeks
Arm/Group Title	Observation Period (Phase 1)		Warfarin Anticoagulation (Phase 2
Arm/Group Description	Phase 1, Observation Period Phase 1 of the study consisted of 8 weeks of observation, which commenced following a baseline visit at week 0.		Phase 2, Treatment Period Anticoagulated with warfarin to maintain an INR of 2-3 between 8 and 16 weeks (treatment period). A single adverse event was noted in one subject during the anticoagulation period. This was classed as minor in severity and related to an episode of minor haemorrhage secondary to an episode of gingivitis, which resolved following antibiotics and did not require blood transfusion, but did require cessation of the anticoagulation for a short period of 2 days. This patient was not included in the analysis. No other subjects required cessation of treatment during the anticoagulation period.
All Cause Mortality
	Observation Period (Phase 1)		Warfarin Anticoagulation (Phase 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/9 (0%)
Serious Adverse Events
	Observation Period (Phase 1)		Warfarin Anticoagulation (Phase 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/9 (0%)
Other (Not Including Serious) Adverse Events
	Observation Period (Phase 1)		Warfarin Anticoagulation (Phase 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		1/9 (11.1%)
General disorders
Minor haemorrhage	0/10 (0%)	0	1/9 (11.1%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.