CIRROX: Phlebotomy and Risk of Hepatocellular Carcinoma in Patients With Compensated Alcoholic Cirrhosis

Sponsor

Assistance Publique - Hôpitaux de Paris (Other)

Overall Status

Terminated

CT.gov ID

NCT01342705

Collaborator

(none)

Enrollment

Locations

Arms

Duration (Months)

1.2

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The main objective of the study is to assess in patients with compensated alcoholic cirrhosis and hepatic iron overload (HIO), as assessed by MRI, the effect of phlebotomy in order to lower and maintain serum ferritin below 50 µg / l on the risk of hepatocellular carcinoma (HCC) occurrence. The effect of bloodletting will be jointly evaluated on 1) episodes of hepatic decompensation, 2) non HCC liver-related mortality 3) changes in HIO during follow-up.

Condition or Disease	Intervention/Treatment	Phase
Alcoholic Cirrhosis Iron Overload	Procedure: phlebotomy	Phase 3

Detailed Description

Purpose

The role of iron in liver carcinogenesis is supported by human, animal and cellular models through direct and indirect mechanisms. The accumulation of iron promotes liver cell proliferation and is responsible for direct structural damage or mutations of DNA caused by free iron itself or reactive oxygen species generated by its accumulation in the liver.

The influence of hepatic iron overload (HIO) on the risk of hepatocellular carcinoma (HCC) is well established in patients with genetic hemochromatosis or HCC developed on non-cirrhotic liver. However, the influence of HIO on the risk of occurrence of HCC in other chronic liver disease (including alcoholic and viral C) has been controversial. Recently, a prospective study including a large population of patients with cirrhosis (n = 301) classified according to the aetiology of liver disease (alcohol, n = 162 or hepatitis C virus (HCV)infection, n = 139) has shown the association between HIO and the occurrence of HCC in patients with alcoholic cirrhosis. Thus, the assessment of liver iron in routine clinical practice could allow the identification of patients at higher risk of developing HCC and in whom preventive measures such as iron depletion by phlebotomy could be undertaken. Based on the model of genetic hemochromatosis in which its effectiveness on survival improvement and even regression of hepatic injury has been shown, its effectiveness on the prognosis and prevention of HCC occurrence in patients with alcoholic cirrhosis must now be studied in prospective multicentre randomized trials.

The main objective of the study is to assess in patients with compensated alcoholic cirrhosis and HIO, as assessed by MRI, the effect of phlebotomy in order to lower and maintain serum ferritin below 50 µg / l on the risk of HCC occurrence. The effect of bloodletting will be jointly evaluated on 1) episodes of hepatic decompensation, 2) non HCC liver-related mortality 3) changes in HIO during follow-up.

Study Type: Interventional Study Design: Allocation: Randomized Endpoint Classification:

Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose:

Prevention

Study Design

Study Type:

Interventional

Actual Enrollment :

17 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

Influence of Iron Depletion by Phlebotomy on the Risk of Hepatocellular Carcinoma Occurrence in Patients With Compensated Alcoholic Cirrhosis. Prospective, Multicentre, Randomized Trial

Study Start Date :

May 1, 2011

Actual Primary Completion Date :

Jun 1, 2014

Actual Study Completion Date :

Jun 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: phlebotomy	Procedure: phlebotomy Procedure: Phlebotomy of 4 ml / kg to obtain (1 phlebotomy every 14 days) and maintain (1 phlebotomy every 3 months) a serum ferritin below 50 µg / l. Other Names: Bloodletting Iron depletion
No Intervention: control

Arm

Intervention/Treatment

Experimental: phlebotomy

Procedure: phlebotomy

Procedure: Phlebotomy of 4 ml / kg to obtain (1 phlebotomy every 14 days) and maintain (1 phlebotomy every 3 months) a serum ferritin below 50 µg / l.

Other Names:

Bloodletting

Iron depletion

No Intervention: control

Outcome Measures

Primary Outcome Measures

Cumulative incidence of HepatoCellular Carcinoma during follow-up [3 years]
the cumulative incidence of HCC will be estimated considering death prior to the event of interest as competing risk outcomes

Secondary Outcome Measures

Number of hepatic decompensation episodes in study participants [3 years]
Cumulative incidence of death non related to hepatoCellular Carcinoma [3 years]
Number of Participants with Adverse Events as a Measure of Safety and Tolerability [3 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age over 18
Biopsy-proven alcoholic cirrhosis
No previous HCC (treated or not)
Excessive alcohol consumption, defined by more than 21 glasses weekly in women and more than 28 glasses weekly in men for at least 10 years, and considered as the main cause for liver cirrhosis
Signed written informed consent
Hepatic iron overload assessed by MRI (Iron hepatic concentration ≥ 80 μmol/g)

Exclusion Criteria:

Subjects deprived of their liberty by judicial or administrative decision
Pregnant women
Serious associated short-term life threatening disease (except HIV viral co-infection, or the liver disease itself)
Impossibility of monitoring, whatever the reason.
Contraindication of phlebotomy
Haemoglobin <13.5 g/dL for men and <12.5g/dL for women (threshold established by the French Blood Agency)
Congestive heart failure or coronary heart disease
Hepatic failure (TP<60%), renal failure (GFR <50 ml/min) or respiratory insufficiency (chronic dyspnea)
Poor venous system
Complication of cirrhosis at time of inclusion (defined as bleeding related to portal hypertension, encephalopathy or ascites)
Presence of hepatitis B or hepatitis C co-infection
Presence of liver focal lesion suggestive of HCC
Child-Pugh score greater than or equal to 7 (Class B or C) at time of inclusion

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Amiens University Hospital :	Amiens	France
2	Avicenne	Bobigny	France
3	Jean Verdier	Bondy	France	93140
4	CHU Bordeaux univerity hospital 1	Bordeaux	France
5	CHU Bordeaux University hospital 2	Bordeaux	France
6	CHU	Caen	France
7	Antoine Béclère	Clamart	France
8	CHU	Grenoble	France
9	CHU	Lille	France
10	CHU	Montpellier	France
11	CHU	Nancy	France
12	CHU	Nice	France
13	CHU	Rennes	France
14	CHU	Rouen	France