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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

Primary Purpose

Nonalcoholic Fatty Liver Disease

Status
Unknown status
Phase
Phase 3
Locations
Italy
Study Type
Interventional
Intervention
Iron depletion treatment
Sponsored by
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Nonalcoholic Fatty Liver Disease focused on measuring Nonalcoholic fatty liver disease associated with increased iron stores

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • U.O. Medicina Interna 1/BRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

1

Arm Description

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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.

Full Information

First Posted
April 9, 2008
Last Updated
April 11, 2008
Sponsor
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
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1. Study Identification

Unique Protocol Identification Number
NCT00658164
Brief Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
July 2007
Overall Recruitment Status
Unknown status
Study Start Date
October 2007 (undefined)
Primary Completion Date
March 2009 (Anticipated)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Name of the Sponsor
Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

4. Oversight

5. Study Description

Brief 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Nonalcoholic Fatty Liver Disease
Keywords
Nonalcoholic fatty liver disease associated with increased iron stores

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
150 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Experimental
Intervention Type
Other
Intervention Name(s)
Iron depletion treatment
Intervention Description
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
Primary Outcome Measure Information:
Title
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
Time Frame
24 months
Secondary Outcome Measure Information:
Title
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.
Time Frame
24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Silvia Fargion, prof
Phone
39-02-5503-3301
Email
silvia.fargion@unimi.it
Facility Information:
Facility Name
U.O. Medicina Interna 1/B
City
Milan
ZIP/Postal Code
20122
Country
Italy
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Silvia Fargion, Prof.
Phone
39-02-5503-3301
Email
silvia.fargion@unimi.it
First Name & Middle Initial & Last Name & Degree
Silvia Fargion, Prof.
First Name & Middle Initial & Last Name & Degree
Luca Valenti, Md

12. IPD Sharing Statement

Learn more about this trial

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

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