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The Potential Hepatoprotective Effect of Metformin in Patients With Beta Thalassemia Major

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ClinicalTrials.gov Identifier: NCT02984475
Recruitment Status : Unknown
Verified July 2018 by Mona Sobhy Abd El-Mon'em Gaber, Cairo University.
Recruitment status was:  Recruiting
First Posted : December 7, 2016
Last Update Posted : July 18, 2018
Sponsor:
Information provided by (Responsible Party):
Mona Sobhy Abd El-Mon'em Gaber, Cairo University

Tracking Information
First Submitted Date  ICMJE November 25, 2016
First Posted Date  ICMJE December 7, 2016
Last Update Posted Date July 18, 2018
Study Start Date  ICMJE December 2016
Estimated Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 25, 2018)
liver enzymes tests. [ Time Frame: 6 months ]
Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST).
Original Primary Outcome Measures  ICMJE
 (submitted: December 6, 2016)
  • liver enzymes and function tests. [ Time Frame: 6 months ]
    ALT.
  • AST [ Time Frame: 6 months ]
  • ALP [ Time Frame: 6 months ]
  • GGT [ Time Frame: 6 months ]
  • total and direct bilirubin. [ Time Frame: 6 months ]
  • Albumin. [ Time Frame: 6 months ]
  • INR [ Time Frame: 6 months ]
  • oxidative stress markers. [ Time Frame: 6 months ]
    MDA
  • TAC [ Time Frame: 6 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 25, 2018)
  • Metformin Safety - Number of participants with treatment-related adverse events [ Time Frame: 6 months ]
    Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
  • liver enzymes and function tests - Alkaline phosphatase (ALP). [ Time Frame: 6 months. ]
    Alkaline phosphatase (ALP).
  • liver enzymes and function tests - Gama-Glutamyl transferase (GGT). [ Time Frame: 6 months. ]
    Gama-Glutamyl transferase (GGT).
  • liver enzymes and function tests - total and direct bilirubin. [ Time Frame: 6 months. ]
    total and direct bilirubin.
  • liver enzymes and function tests - Albumin. [ Time Frame: 6 months. ]
    Albumin .
  • liver enzymes and function tests - International Normalized Ratio (INR). [ Time Frame: 6 months. ]
    International Normalized Ratio (INR).
  • oxidative stress markers (MDA). [ Time Frame: 6 months. ]
    Malondialdehyde (MDA)
  • oxidative stress markers (TAC). [ Time Frame: 6 months. ]
    Total antioxidant capacity (TAC).
Original Secondary Outcome Measures  ICMJE
 (submitted: December 6, 2016)
Metformin Safety - Number of participants with treatment-related adverse events [ Time Frame: 6 months ]
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
Current Other Pre-specified Outcome Measures
 (submitted: January 25, 2018)
  • Fibroscan. [ Time Frame: 6 months ]
    Fibroscan will be done for each patient before and at the end of the study.
  • FIB 4 score. [ Time Frame: 6 months ]
    Fibrosis 4 score.
  • APRI score. [ Time Frame: 6 months ]
    AST to platelet ratio index score.
Original Other Pre-specified Outcome Measures
 (submitted: December 6, 2016)
  • Fibroscan. [ Time Frame: 6 months ]
  • FIB 4 score. [ Time Frame: 6 months ]
  • APRI score. [ Time Frame: 6 months ]
 
Descriptive Information
Brief Title  ICMJE The Potential Hepatoprotective Effect of Metformin in Patients With Beta Thalassemia Major
Official Title  ICMJE The Potential Hepatoprotective Effect of Metformin in Patients With Beta Thalasemia Major
Brief Summary

Beta Thalassemia is a major public health problem in Mediterranean countries.In Egypt, it is considered as the most common chronic hemolytic anemia.one of the major complications in this inherited disorder is iron overload which lead to oxidative stress and tissue damage.

Regarding toxic effect of iron overload on liver, hepatomegaly is one of the most findings that resulting from hemosiderosis, extra medullary hematopoiesis, transmitted hepatitis B and C and cirrhosis.

A lot of studies have been carried out recently to study the beneficial role of metformin in non-diabetic patients of different disorders as non-alcoholic fatty liver disease (NAFLD).Among several studies, it's demonstrated that metformin significantly improved insulin resistance, aminotransferase levels and liver morphology.

The role of metformin in these studies is mainly thought to be antioxidant and anti-inflammatory effects. However, the role of Metformin on hepatic function in different populations with the same mechanism of liver injury should be further investigated.

This clinical trial will be carried out on 60 patients with beta thalassemia major receiving regular blood transfusion and iron chelating therapy, either HCV positive or negative patients.

They will be randomly distributed into either control group (group 1, n=30) receiving blood transfusion and taking iron chelating therapy or treatment group (group 2, n=30) receiving blood transfusion and taking iron chelating therapy along with metformin tablets (500 mg/twice daily) for 6 months.

Detailed Description

Beta-Thalassemia is a major public health problem in Mediterranean countries , parts of North and West Africa, the Middle East, the Indian subcontinent, southern Far East and southeastern Asia is of the highest incidence. In Egypt, it is considered as the most common chronic hemolytic anemia (85.1%) with 5.3- 9% carrier rate and annual birth of 1000/1.5 million live births. Thalassemia is a heterogeneous group of hereditary anemia that results from reduced or absent production of alpha or beta globin chains of hemoglobin A. β-thalassemia patients have partial or complete lack of production of β-chains of hemoglobin. The remaining excess of α-chains are unstable, and they finally precipitate and disintegrate, causing red blood cell (RBC) membrane damage. The affected RBCs are prematurely hemolysed in the spleen and bone marrow, leading to increased RBC turnover, ineffective erythropoiesis, and severe anemia that can only be controlled by regular blood transfusion.

One of the major complications in this inherited disorder is iron overload because of premature hemolysis, ineffective erythropoiesis and repeated transfusion in the plasma and major organs such as heart, liver, and endocrine glands. Iron has a catalytic role to produce powerful reactive oxidant species (ROS) and free radicals, which lead to oxidative stress and damage . Children with beta thalassemia have oxidative stress and antioxidant deficiency even without iron overload status. The only way to avoid the accumulation of potentially toxic iron is iron chelation along with the transfusional therapy, desferrioxamine is a chelating agent that has been discovered 30 years ago and since then it has been considered to be one of the most important chelating agent that have been extensively used in the clinical practice . Then other iron chelating agents have been discovered as deferasirox (Exjade®) and deferiprone (Kelfer®). However, there are a lot of problems regarding the compliance to desferrioxamine regimen and the side effects of other orally active iron chelating agents, which rises the need for studying the effect of other naturally occurring iron chelating agents and supplements to reduce the consequences of the iron overload. As reactive oxygen species (ROS) and iron overload have an important role in the pathophysiology of thalassemia , some studies have been carried out to determine the effects of supplements such as silymarin and vitamin E in thalassemic patients on regular blood transfusion and desferrioxamine, and they showing benefit due to their antioxidant, cytoprotective, and iron-chelating activities .

Regarding the toxic effect of iron overload on liver, hepatomegaly is one of the most findings that resulting from hemosiderosis, extra medullary hematopoiesis, transmitted hepatitis B and C and cirrhosis . In one study, liver function tests (LFT) and serum ferritin were elevated in most patients in spite of desferoxamine use .

Metformin (Biguanides) is used as a first-line treatment for patients with type 2 diabetes mellitus . But it is not the only use of metformin, a lot of studies have been carried out recently to study the beneficial role of metformin in non-diabetic patients of different disorders. Metformin was shown to be safe and effective for management of type 2 diabetes in pediatric patients aged 10-16 years old, initiated dose of 500 mg twice daily and titrated up to a maximum of 2000 mg/day based on response . Several clinical studies have supported the beneficial role of metformin in patients with non-alcoholic fatty liver disease (NAFLD) . Most of these studies have evaluated the effect of different doses of metformin on liver biochemistry (aminotransferase profile), histology, and metabolic syndrome feature . Among several studies, it's demonstrated that metformin significantly improved insulin resistance, aminotransferase levels, and liver morphology. Furthermore, in ob/ob mice, a model of hepatic steatosis, it has been shown that metformin reversed hepatomegaly, hepatic fat accumulation, and ALT abnormalities, by reducing hepatic tumor necrosis factor-α (TNF-α) expression . Also the hepatoprotective effect of metformin on methotrexate-induced hepatotoxicity in rabbits with acute lymphocytic leukemia (ALL) has been established. The role of metformin in these studies is mainly thought to be antioxidant and anti-inflammatory effects. However, the role of Metformin on hepatic function in different populations with the same mechanism of liver injury should be further investigated.

This study is conducted to determine the safety and efficacy of metformin as hepatoprotective and antioxidant therapy in iron overloaded patients with Beta-Thalassemia Major.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Beta Thalassemia Major Anemia
Intervention  ICMJE Drug: Metformin
Other Name: Cidophage
Study Arms  ICMJE
  • Active Comparator: treatment arm
    30 patients receiving blood transfusion and taking iron-chelating therapy along with metformin tablets (500 mg once daily for the first week then twice daily for 6 months).
    Intervention: Drug: Metformin
  • No Intervention: control arm
    30 patients receiving blood transfusion and taking iron-chelating therapy.
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: December 6, 2016)
60
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 2019
Estimated Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Diagnosed with Beta-Thalassemia Major and receiving regular blood transfusion and on iron chelating therapy.
  • Weight: equal to or over 35 kg.
  • Normal renal function.

Exclusion Criteria:

  • Patients with renal impairment (serum creatinine more than twice the upper limit of normal).
  • Patients with heart failure.
  • Patients with sepsis or active infection.
  • Patients with diabetes mellitus (either primary or secondary to thalassemia).
  • regular consumption of medication with potential hepatotoxicity.
  • regular herbal medicine or antioxidant supplementation.
  • patients with gastrointestinal conditions preventing adsorption of oral medication.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 11 Years to 18 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Egypt
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02984475
Other Study ID Numbers  ICMJE CL 1726
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Mona Sobhy Abd El-Mon'em Gaber, Cairo University
Study Sponsor  ICMJE Cairo University
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Cairo University
Verification Date July 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP