<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02984475</url>
  </required_header>
  <id_info>
    <org_study_id>CL 1726</org_study_id>
    <nct_id>NCT02984475</nct_id>
  </id_info>
  <brief_title>The Potential Hepatoprotective Effect of Metformin in Patients With Beta Thalassemia Major</brief_title>
  <official_title>The Potential Hepatoprotective Effect of Metformin in Patients With Beta Thalasemia Major</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cairo University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Cairo University</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Beta Thalassemia is a major public health problem in Mediterranean countries.In Egypt, it is&#xD;
      considered as the most common chronic hemolytic anemia.one of the major complications in this&#xD;
      inherited disorder is iron overload which lead to oxidative stress and tissue damage.&#xD;
&#xD;
      Regarding toxic effect of iron overload on liver, hepatomegaly is one of the most findings&#xD;
      that resulting from hemosiderosis, extra medullary hematopoiesis, transmitted hepatitis B and&#xD;
      C and cirrhosis.&#xD;
&#xD;
      A lot of studies have been carried out recently to study the beneficial role of metformin in&#xD;
      non-diabetic patients of different disorders as non-alcoholic fatty liver disease&#xD;
      (NAFLD).Among several studies, it's demonstrated that metformin significantly improved&#xD;
      insulin resistance, aminotransferase levels and liver morphology.&#xD;
&#xD;
      The role of metformin in these studies is mainly thought to be antioxidant and&#xD;
      anti-inflammatory effects. However, the role of Metformin on hepatic function in different&#xD;
      populations with the same mechanism of liver injury should be further investigated.&#xD;
&#xD;
      This clinical trial will be carried out on 60 patients with beta thalassemia major receiving&#xD;
      regular blood transfusion and iron chelating therapy, either HCV positive or negative&#xD;
      patients.&#xD;
&#xD;
      They will be randomly distributed into either control group (group 1, n=30) receiving blood&#xD;
      transfusion and taking iron chelating therapy or treatment group (group 2, n=30) receiving&#xD;
      blood transfusion and taking iron chelating therapy along with metformin tablets (500&#xD;
      mg/twice daily) for 6 months.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Beta-Thalassemia is a major public health problem in Mediterranean countries , parts of North&#xD;
      and West Africa, the Middle East, the Indian subcontinent, southern Far East and southeastern&#xD;
      Asia is of the highest incidence. In Egypt, it is considered as the most common chronic&#xD;
      hemolytic anemia (85.1%) with 5.3- 9% carrier rate and annual birth of 1000/1.5 million live&#xD;
      births. Thalassemia is a heterogeneous group of hereditary anemia that results from reduced&#xD;
      or absent production of alpha or beta globin chains of hemoglobin A. β-thalassemia patients&#xD;
      have partial or complete lack of production of β-chains of hemoglobin. The remaining excess&#xD;
      of α-chains are unstable, and they finally precipitate and disintegrate, causing red blood&#xD;
      cell (RBC) membrane damage. The affected RBCs are prematurely hemolysed in the spleen and&#xD;
      bone marrow, leading to increased RBC turnover, ineffective erythropoiesis, and severe anemia&#xD;
      that can only be controlled by regular blood transfusion.&#xD;
&#xD;
      One of the major complications in this inherited disorder is iron overload because of&#xD;
      premature hemolysis, ineffective erythropoiesis and repeated transfusion in the plasma and&#xD;
      major organs such as heart, liver, and endocrine glands. Iron has a catalytic role to produce&#xD;
      powerful reactive oxidant species (ROS) and free radicals, which lead to oxidative stress and&#xD;
      damage . Children with beta thalassemia have oxidative stress and antioxidant deficiency even&#xD;
      without iron overload status. The only way to avoid the accumulation of potentially toxic&#xD;
      iron is iron chelation along with the transfusional therapy, desferrioxamine is a chelating&#xD;
      agent that has been discovered 30 years ago and since then it has been considered to be one&#xD;
      of the most important chelating agent that have been extensively used in the clinical&#xD;
      practice . Then other iron chelating agents have been discovered as deferasirox (Exjade®) and&#xD;
      deferiprone (Kelfer®). However, there are a lot of problems regarding the compliance to&#xD;
      desferrioxamine regimen and the side effects of other orally active iron chelating agents,&#xD;
      which rises the need for studying the effect of other naturally occurring iron chelating&#xD;
      agents and supplements to reduce the consequences of the iron overload. As reactive oxygen&#xD;
      species (ROS) and iron overload have an important role in the pathophysiology of thalassemia&#xD;
      , some studies have been carried out to determine the effects of supplements such as&#xD;
      silymarin and vitamin E in thalassemic patients on regular blood transfusion and&#xD;
      desferrioxamine, and they showing benefit due to their antioxidant, cytoprotective, and&#xD;
      iron-chelating activities .&#xD;
&#xD;
      Regarding the toxic effect of iron overload on liver, hepatomegaly is one of the most&#xD;
      findings that resulting from hemosiderosis, extra medullary hematopoiesis, transmitted&#xD;
      hepatitis B and C and cirrhosis . In one study, liver function tests (LFT) and serum ferritin&#xD;
      were elevated in most patients in spite of desferoxamine use .&#xD;
&#xD;
      Metformin (Biguanides) is used as a first-line treatment for patients with type 2 diabetes&#xD;
      mellitus . But it is not the only use of metformin, a lot of studies have been carried out&#xD;
      recently to study the beneficial role of metformin in non-diabetic patients of different&#xD;
      disorders. Metformin was shown to be safe and effective for management of type 2 diabetes in&#xD;
      pediatric patients aged 10-16 years old, initiated dose of 500 mg twice daily and titrated up&#xD;
      to a maximum of 2000 mg/day based on response . Several clinical studies have supported the&#xD;
      beneficial role of metformin in patients with non-alcoholic fatty liver disease (NAFLD) .&#xD;
      Most of these studies have evaluated the effect of different doses of metformin on liver&#xD;
      biochemistry (aminotransferase profile), histology, and metabolic syndrome feature . Among&#xD;
      several studies, it's demonstrated that metformin significantly improved insulin resistance,&#xD;
      aminotransferase levels, and liver morphology. Furthermore, in ob/ob mice, a model of hepatic&#xD;
      steatosis, it has been shown that metformin reversed hepatomegaly, hepatic fat accumulation,&#xD;
      and ALT abnormalities, by reducing hepatic tumor necrosis factor-α (TNF-α) expression . Also&#xD;
      the hepatoprotective effect of metformin on methotrexate-induced hepatotoxicity in rabbits&#xD;
      with acute lymphocytic leukemia (ALL) has been established. The role of metformin in these&#xD;
      studies is mainly thought to be antioxidant and anti-inflammatory effects. However, the role&#xD;
      of Metformin on hepatic function in different populations with the same mechanism of liver&#xD;
      injury should be further investigated.&#xD;
&#xD;
      This study is conducted to determine the safety and efficacy of metformin as hepatoprotective&#xD;
      and antioxidant therapy in iron overloaded patients with Beta-Thalassemia Major.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>December 2016</start_date>
  <completion_date type="Anticipated">April 2019</completion_date>
  <primary_completion_date type="Anticipated">December 2018</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>liver enzymes tests.</measure>
    <time_frame>6 months</time_frame>
    <description>Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Metformin Safety - Number of participants with treatment-related adverse events</measure>
    <time_frame>6 months</time_frame>
    <description>Number of participants with treatment-related adverse events as assessed by CTCAE v4.0</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>liver enzymes and function tests - Alkaline phosphatase (ALP).</measure>
    <time_frame>6 months.</time_frame>
    <description>Alkaline phosphatase (ALP).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>liver enzymes and function tests - Gama-Glutamyl transferase (GGT).</measure>
    <time_frame>6 months.</time_frame>
    <description>Gama-Glutamyl transferase (GGT).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>liver enzymes and function tests - total and direct bilirubin.</measure>
    <time_frame>6 months.</time_frame>
    <description>total and direct bilirubin.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>liver enzymes and function tests - Albumin.</measure>
    <time_frame>6 months.</time_frame>
    <description>Albumin .</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>liver enzymes and function tests - International Normalized Ratio (INR).</measure>
    <time_frame>6 months.</time_frame>
    <description>International Normalized Ratio (INR).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>oxidative stress markers (MDA).</measure>
    <time_frame>6 months.</time_frame>
    <description>Malondialdehyde (MDA)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>oxidative stress markers (TAC).</measure>
    <time_frame>6 months.</time_frame>
    <description>Total antioxidant capacity (TAC).</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Fibroscan.</measure>
    <time_frame>6 months</time_frame>
    <description>Fibroscan will be done for each patient before and at the end of the study.</description>
  </other_outcome>
  <other_outcome>
    <measure>FIB 4 score.</measure>
    <time_frame>6 months</time_frame>
    <description>Fibrosis 4 score.</description>
  </other_outcome>
  <other_outcome>
    <measure>APRI score.</measure>
    <time_frame>6 months</time_frame>
    <description>AST to platelet ratio index score.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Beta Thalassemia Major Anemia</condition>
  <arm_group>
    <arm_group_label>treatment arm</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>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).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>control arm</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>30 patients receiving blood transfusion and taking iron-chelating therapy.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metformin</intervention_name>
    <arm_group_label>treatment arm</arm_group_label>
    <other_name>Cidophage</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diagnosed with Beta-Thalassemia Major and receiving regular blood transfusion and on&#xD;
             iron chelating therapy.&#xD;
&#xD;
          -  Weight: equal to or over 35 kg.&#xD;
&#xD;
          -  Normal renal function.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with renal impairment (serum creatinine more than twice the upper limit of&#xD;
             normal).&#xD;
&#xD;
          -  Patients with heart failure.&#xD;
&#xD;
          -  Patients with sepsis or active infection.&#xD;
&#xD;
          -  Patients with diabetes mellitus (either primary or secondary to thalassemia).&#xD;
&#xD;
          -  regular consumption of medication with potential hepatotoxicity.&#xD;
&#xD;
          -  regular herbal medicine or antioxidant supplementation.&#xD;
&#xD;
          -  patients with gastrointestinal conditions preventing adsorption of oral medication.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>11 Years</minimum_age>
    <maximum_age>18 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Abo El Reesh Hospital</name>
      <address>
        <city>Cairo.</city>
        <country>Egypt</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Mona Gaber, Bachelor.</last_name>
      <phone>0223648368</phone>
      <email>mona.sobhy@pharma.cu.edu.eg</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>El Demerdash (Ain Shams Teaching Hospital).</name>
      <address>
        <city>Cairo.</city>
        <country>Egypt</country>
      </address>
    </facility>
    <status>Completed</status>
  </location>
  <location_countries>
    <country>Egypt</country>
  </location_countries>
  <verification_date>July 2018</verification_date>
  <study_first_submitted>November 25, 2016</study_first_submitted>
  <study_first_submitted_qc>December 6, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 7, 2016</study_first_posted>
  <last_update_submitted>July 16, 2018</last_update_submitted>
  <last_update_submitted_qc>July 16, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">July 18, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Cairo University</investigator_affiliation>
    <investigator_full_name>Mona Sobhy Abd El-Mon'em Gaber</investigator_full_name>
    <investigator_title>Teaching assistant-faculty of pharmacy-Cairo University</investigator_title>
  </responsible_party>
  <keyword>Beta Thalassemia</keyword>
  <keyword>Metformin</keyword>
  <keyword>Oxidative stress</keyword>
  <keyword>Iron overload</keyword>
  <keyword>Liver function</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Thalassemia</mesh_term>
    <mesh_term>beta-Thalassemia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Metformin</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02984475
org study id: CL 1726
nct id: NCT02984475
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
is us export: No
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.
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: liver enzymes tests.
time frame: 6 months
description: Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST).
measure: Metformin Safety - Number of participants with treatment-related adverse events
time frame: 6 months
description: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
measure: liver enzymes and function tests - Alkaline phosphatase (ALP).
time frame: 6 months.
description: Alkaline phosphatase (ALP).
measure: liver enzymes and function tests - Gama-Glutamyl transferase (GGT).
time frame: 6 months.
description: Gama-Glutamyl transferase (GGT).
measure: liver enzymes and function tests - total and direct bilirubin.
time frame: 6 months.
description: total and direct bilirubin.
measure: liver enzymes and function tests - Albumin.
time frame: 6 months.
description: Albumin .
measure: liver enzymes and function tests - International Normalized Ratio (INR).
time frame: 6 months.
description: International Normalized Ratio (INR).
measure: oxidative stress markers (MDA).
time frame: 6 months.
description: Malondialdehyde (MDA)
measure: oxidative stress markers (TAC).
time frame: 6 months.
description: Total antioxidant capacity (TAC).
measure: Fibroscan.
time frame: 6 months
description: Fibroscan will be done for each patient before and at the end of the study.
measure: FIB 4 score.
time frame: 6 months
description: Fibrosis 4 score.
measure: APRI score.
time frame: 6 months
description: AST to platelet ratio index score.
arm group label: treatment arm
arm group type: Active Comparator
description: 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).
arm group label: control arm
arm group type: No Intervention
description: 30 patients receiving blood transfusion and taking iron-chelating therapy.
intervention type: Drug
intervention name: Metformin
arm group label: treatment arm
other name: Cidophage
criteria: 
gender: All
minimum age: 11 Years
maximum age: 18 Years
healthy volunteers: No
facility: 
status: Recruiting
contact: 
facility: 
status: Completed
country: Egypt
responsible party type: Principal Investigator
investigator affiliation: Cairo University
investigator full name: Mona Sobhy Abd El-Mon'em Gaber
investigator title: Teaching assistant-faculty of pharmacy-Cairo University
mesh term: Thalassemia
mesh term: beta-Thalassemia
mesh term: Metformin