Effect of Iron Depletion by Phlebotomy Plus Lifestyle Changes vs. Lifestyle Changes Alone on Liver Damage in Patients With Nonalcoholic Fatty Liver Disease With Increased Iron Stores

Nonalcoholic Fatty Liver Disease Clinical Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00658164
• Other study ID #: 111.2007
• Status: Recruiting
• Phase: Phase 3
• First received: April 9, 2008
• Last updated: April 11, 2008
• Start date: October 2007

Study information

• Verified date: July 2007
• Source: Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
• Contact: Silvia Fargion, prof
• Phone: 39-02-5503-3301
• Email: silvia.fargion[@]unimi.it
• Is FDA regulated: No
• Health authority: Italy: Fondazione IRCCS Ospedale Maggiore Policlinico Mangiagalli e Regina Elena
• Study type: Interventional

Clinical Trial Summary

Patients will be randomized to lifestyle changes alone or lifestyle changes associated with iron depletion.

Iron depletion will be achieved by removing 350 cc of blood every 10-15 days according to baseline hemoglobin values and venesection tolerance, until ferritin < 30 ng/ml and transferrin saturation < 25%. Weekly phlebotomies will be allowed for carriers of the C282Y HFE mutation. Smaller phlebotomies (250 cc) will be allowed for carriers of beta-thalassaemia trait. Maintenance phlebotomies (as much as required) will then be instituted to keep iron stores depleted (ferritin < 50 ng/ml and transferrin saturation < 25%, MCV <85 fl). Before starting treatment, patients will undergo ECG, and in the presence of hyperglycemia or hypertension also echocardiography (see exclusion criteria).

Change in diabetes medication dosage or start of new therapy will be allowed for HbA1C values <6% or ≥ 7%. According to accepted criteria, previously untreated patients should be treated with metformin. If possible, newly diagnosed hypertension should be treated with Ace-inhibitors.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 150
• Est. primary completion date: March 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• Age = 18 < 75 years

• Ferritin > 250 ng/ml and/or stainable iron at biopsy

• NAS = 2 and/or NAS 1 and stage=1 at liver histology

• Willingness to maintain diet and exercise during the full course of the study

• Written informed consent to participate to the study and to have the specific genetic tests performed

• Ability to comply with all study requirements

Exclusion Criteria:

• Pregnant or lactating female

• Diagnosis of or a history of:

• Type 1 diabetes, diabetes that is a result of pancreatic injury, or secondary forms of diabetes, e.g. Cushing's syndrome or acromegaly

• Acute metabolic complication such as ketoacidosis or hyperosmolar state within the past 6 months

• Alcohol consumption > 20 g/day for females and > 30 g/day for males

• BMI = 35 Kg/ m2

• Other liver disease such as viral hepatitis, autoimmune hepatitis, Wilson disease, as defined by ceruloplasmin below normal limits and liver histology consistent with Wilson disease. Alpha-1-antitrypsin deficiency as defined by alpha-1-antitrypsin level less than 80 mg/dl or PiZ/PiZ or PiZ/PiS genotype. *Hemochromatosis, as defined by homozygosity for the C282Y HFE mutation or compound heterozygosity for C282Y/H63D mutations or Hepatic Iron Index = 1.9.

• Advanced liver disease (Child B/C cirrhosis), portal hypertension, hepatocellular carcinoma.

• Congestive heart failure (NYHA I-IV) and unstable ischemic heart disease, systolic dysfunction (ejection fraction < 45%)

• Any of the following ECG abnormalities: II or III degree Atrial Ventricular *Block, QT>500msec, repolarization defect suggestive of ischemia

• Malignancy within the last 5 years

• Serum creatinine levels > 1.5 mg/dl males, > 1.4 mg/dl females

• TSH outside of normal range

• Use of drugs known to induce NAFLD: corticosteroids, methotrexate, zidovudine, amiodarone, GH, estrogens, tamoxifene, tetracycline

• Lipodystrophy, dysbetalipoproteinemia, inflammatory bowel disease, HIV infection

• Basal hemoglobin levels < 11 g/dl

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Fatty Liver
• Liver Diseases
• Nonalcoholic Fatty Liver Disease

Intervention

Other:
• Iron depletion treatment
Effect of iron depletion by phlebotomy plus lifestyle changes vs. lifestyle changes alone on liver damage in patients with nonalcoholic fatty liver disease with increased iron stores

Locations

Country	Name	City	State
Italy	U.O. Medicina Interna 1/B	Milan

Sponsors (1)

Lead Sponsor	Collaborator
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

Country where clinical trial is conducted

Italy, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To determine in a 24 month controlled study whether iron depletion by phlebotomy improves insulin sensitivity, and thereby reduces hepatic steatosis and inflammation in subjects with nonalcoholic steatohepatitis		24 months	No
Secondary	To assess the effect of iron depletion on glucose tolerance status. Glucose tolerance will be determined by OGTT in subjects without type 2 diabetes (T2D), and by HbA1c levels and the change in dosage of pharmacological therapy in those with T2D.		24 months	No