Clinical trial NCT01342705: Phlebotomy and Risk of Hepatocellular Carcinoma in Patients With Compensated Alcoholic Cirrhosis
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 type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Alcoholic Cirrhosis
Iron Overload
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2011-04-27
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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

Eligibility criteria: 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

Primary outcomes:
measure: Cumulative incidence of HepatoCellular Carcinoma during follow-up
timeFrame: 3 years
Secondary outcomes:
measure: Number of hepatic decompensation episodes in study participants
timeFrame: 3 years
measure: Cumulative incidence of death non related to hepatoCellular Carcinoma
timeFrame: 3 years
measure: Number of Participants with Adverse Events as a Measure of Safety and Tolerability
timeFrame: 3 years
Other outcomes:
Locations:
city: Amiens
country: France
facility: Amiens University Hospital :
city: Bobigny
country: France
facility: Avicenne
city: Bondy
country: France
facility: Jean Verdier
city: Bordeaux
country: France
facility: CHU Bordeaux univerity hospital 1
city: Bordeaux
country: France
facility: CHU Bordeaux University hospital 2
city: Caen
country: France
facility: CHU
city: Clamart
country: France
facility: Antoine Béclère
city: Grenoble
country: France
facility: CHU
city: Lille
country: France
facility: CHU
city: Montpellier
country: France
facility: CHU
city: Nancy
country: France
facility: CHU
city: Nice
country: France
facility: CHU
city: Rennes
country: France
facility: CHU
city: Rouen
country: France
facility: CHU
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Pierre NAHON, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: