<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/NCT03840226</url>
  </required_header>
  <id_info>
    <org_study_id>SHEBA-18-5464-MS-CTIL</org_study_id>
    <nct_id>NCT03840226</nct_id>
  </id_info>
  <brief_title>The Impact of Magnesium on Exercise Tolerance, Quality of Life and Clinical Outcomes in Chronic Heart Failure Patients</brief_title>
  <official_title>The Impact of Magnesium Oxide Monohydrate Compared to Placebo on Exercise Tolerance, Quality of Life and Clinical Outcomes in Chronic Heart Failure Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sheba Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Naveh Pharma (1996) Ltd.</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Sheba Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Magnesium supplementation could improve cardiac performance. Patients with chronic heart&#xD;
      failure (CHF) are magnesium deficient and we hypothesized that 1 year supplementation of oral&#xD;
      magnesium comparted to placebo will improve exercise duration time and quality of life.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Magnesium supplementation improves myocardial metabolism, inhibits calcium accumulation and&#xD;
      myocardial cell death; it improves vascular tone, peripheral vascular resistance, afterload&#xD;
      and cardiac output, reduces cardiac arrhythmias and improves lipid metabolism. Magnesium also&#xD;
      reduces vulnerability to oxygen-derived free radicals, improves human endothelial function&#xD;
      and inhibits platelet function. Patients with chronic heart failure (CHF) are magnesium&#xD;
      deficient. The activation of the renin-angiotensin-aldosterone system and the use of&#xD;
      diuretics are associated with depletion of potassium and magnesium in CHF. Magnesium&#xD;
      deficiency stimulates aldosterone production and secretion, while magnesium infusion&#xD;
      decreases aldosterone production production by inhibiting cellular calcium influx.&#xD;
      Adamopoulos et al recently found that CHF in patients [mainly New York Heart Association&#xD;
      (NYHA) II-II] with low serum magnesium ≤ 2 mEq/L was associated with increased cardiovascular&#xD;
      mortality (but had no association with cardiovascular hospitalization) compared to those with&#xD;
      serum magnesium &gt; 2 mEq/L in a long-term follow-up of 36 months, suggesting that most of&#xD;
      these deaths were likely sudden (arrhythmic) in nature.&#xD;
&#xD;
      Furthermore, Stepura and Martynow demonstrated that oral magnesium orotate used as adjuvant&#xD;
      therapy in severe NYHA IV CHF patients increased 1-year survival rate and improved clinical&#xD;
      symptoms and patient's quality of life compared to placebo. The investigators hypothesized&#xD;
      that 1-year supplementation of oral magnesium compared to placebo to CHF patients will&#xD;
      improve exercise duration time and quality of life.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">August 25, 2019</start_date>
  <completion_date type="Anticipated">March 1, 2024</completion_date>
  <primary_completion_date type="Anticipated">January 1, 2024</primary_completion_date>
  <phase>Phase 3</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>
    <intervention_model_description>The aim of the study is to test The impact of magnum versus placebo, on six-minute and clinical outcomes of patients with CHF (level 2-4).&#xD;
The Primary endpoints are:&#xD;
Improvement in Six-Minute walk test.&#xD;
Improvement in clinical outcomes: death, CHF hospitalization, revascularization etc.&#xD;
To test the hypothesis that the six-minute results between the two study groups are different, with significance level of 5% and power of at least 80%, we use the t-test. Based on Monica et al (2001), the mean six-minute results among these patients is 218 with SD=28. for an expected difference of at least 10 meter, we need a sample size of 125 patients in each group.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Improvement in exercise duration time</measure>
    <time_frame>1 year</time_frame>
    <description>Improvement in 6-minute walking testing (any improvemnt of length in meters from baseline). The outcome will be measured in meters and the higher is better from baseline. A 10% higher distance from baseline will be considered significant improvement.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Qaulity of life</measure>
    <time_frame>1 year</time_frame>
    <description>Improvement in quality of life by Minisota living with Heart Failure Questionnaire. The scale is in points and the higher scale the better. Any improvement in at least 10% from baseline will be considered a significant improvement.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Improvment in the number of hospitalizations for heart failure</measure>
    <time_frame>1 year</time_frame>
    <description>All hospitalizations for worsening of heart failure will be counted and recorded and the number of hospitalizations for heart failure will be conted in the magnesium compared to the placebo arms.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">320</enrollment>
  <condition>Magnesium Deficiency</condition>
  <condition>Heart Failure</condition>
  <arm_group>
    <arm_group_label>Magnesium</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>oral magnesium oxide tablets [Magnox 520 TM (magnesium oxide monohydrate, 520 mg/day of elemental magnesium), Naveh Pharma, Israel]</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo tablets</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Oral Tablet</intervention_name>
    <description>Placebo tablets</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Placebo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Magnesium Oxide</intervention_name>
    <description>Magnesium tablets</description>
    <arm_group_label>Magnesium</arm_group_label>
    <other_name>Magnox 520 TM</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  CHF patients NYHA II-IV &gt; 3 months&#xD;
&#xD;
          -  Diuretic therapy &gt; 3 months&#xD;
&#xD;
          -  Signed informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  chronic renal failure (serum creatinine &gt; 3 mg/dL)&#xD;
&#xD;
          -  AMI/ACS&lt; 3 months from randomization&#xD;
&#xD;
          -  Cardiac or other organ transplantation&#xD;
&#xD;
          -  Uncontrolled hypo/hyperthyroidism&#xD;
&#xD;
          -  Chronic diarrhea&#xD;
&#xD;
          -  Life expectancy &lt; 1 year&#xD;
&#xD;
          -  Known psychiatric disease which inhibits patient's enrollment to the study&#xD;
&#xD;
          -  Inability to come for follow-up visits&#xD;
&#xD;
          -  Any planned operation/invasive procedures in the near 6 months&#xD;
&#xD;
          -  Uncontrolled cardiac arrhythmias&#xD;
&#xD;
          -  Inability to perform 6 minute walk testing&#xD;
&#xD;
          -  Any participation in another interventional clinical trial &lt; 1 month from&#xD;
             randomization&#xD;
&#xD;
          -  Any malignancy with life expectancy &lt; 1 year Any AV Block&gt; 2 degree without a&#xD;
             pacemaker&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Michael Shechter, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Sheba Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Michael Shechter, MD</last_name>
    <phone>+97235302617</phone>
    <email>Michael.Shechter@sheba.health.gov.il</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Nava Eizenberg, RN</last_name>
    <phone>+97235302617</phone>
    <email>Nava.Eizenberg@sheba.health.gov.il</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Leviev Heart Center, Chaim Sheba Medical Center</name>
      <address>
        <city>Ramat Gan</city>
        <country>Israel</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Michael Shechter, MD</last_name>
      <phone>+97235302617</phone>
      <email>Michael.Shechter@sheba.health.gov.il</email>
    </contact>
  </location>
  <location_countries>
    <country>Israel</country>
  </location_countries>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>February 9, 2019</study_first_submitted>
  <study_first_submitted_qc>February 12, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 15, 2019</study_first_posted>
  <last_update_submitted>May 3, 2022</last_update_submitted>
  <last_update_submitted_qc>May 3, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 4, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Sheba Medical Center</investigator_affiliation>
    <investigator_full_name>Michael Shechter</investigator_full_name>
    <investigator_title>Director, Clinical Research Unit</investigator_title>
  </responsible_party>
  <keyword>magnesium</keyword>
  <keyword>heart failure</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heart Failure</mesh_term>
    <mesh_term>Magnesium Deficiency</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Magnesium Oxide</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/NCT03840226
org study id: SHEBA-18-5464-MS-CTIL
nct id: NCT03840226
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Magnesium supplementation could improve cardiac performance. Patients with chronic heart
      failure (CHF) are magnesium deficient and we hypothesized that 1 year supplementation of oral
      magnesium comparted to placebo will improve exercise duration time and quality of life.
Magnesium supplementation improves myocardial metabolism, inhibits calcium accumulation and
      myocardial cell death; it improves vascular tone, peripheral vascular resistance, afterload
      and cardiac output, reduces cardiac arrhythmias and improves lipid metabolism. Magnesium also
      reduces vulnerability to oxygen-derived free radicals, improves human endothelial function
      and inhibits platelet function. Patients with chronic heart failure (CHF) are magnesium
      deficient. The activation of the renin-angiotensin-aldosterone system and the use of
      diuretics are associated with depletion of potassium and magnesium in CHF. Magnesium
      deficiency stimulates aldosterone production and secretion, while magnesium infusion
      decreases aldosterone production production by inhibiting cellular calcium influx.
      Adamopoulos et al recently found that CHF in patients [mainly New York Heart Association
      (NYHA) II-II] with low serum magnesium ≤ 2 mEq/L was associated with increased cardiovascular
      mortality (but had no association with cardiovascular hospitalization) compared to those with
      serum magnesium > 2 mEq/L in a long-term follow-up of 36 months, suggesting that most of
      these deaths were likely sudden (arrhythmic) in nature.

      Furthermore, Stepura and Martynow demonstrated that oral magnesium orotate used as adjuvant
      therapy in severe NYHA IV CHF patients increased 1-year survival rate and improved clinical
      symptoms and patient's quality of life compared to placebo. The investigators hypothesized
      that 1-year supplementation of oral magnesium compared to placebo to CHF patients will
      improve exercise duration time and quality of life.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: The aim of the study is to test The impact of magnum versus placebo, on six-minute and clinical outcomes of patients with CHF (level 2-4).
The Primary endpoints are:
Improvement in Six-Minute walk test.
Improvement in clinical outcomes: death, CHF hospitalization, revascularization etc.
To test the hypothesis that the six-minute results between the two study groups are different, with significance level of 5% and power of at least 80%, we use the t-test. Based on Monica et al (2001), the mean six-minute results among these patients is 218 with SD=28. for an expected difference of at least 10 meter, we need a sample size of 125 patients in each group.
primary purpose: Treatment
masking: Single (Participant)
measure: Improvement in exercise duration time
time frame: 1 year
description: Improvement in 6-minute walking testing (any improvemnt of length in meters from baseline). The outcome will be measured in meters and the higher is better from baseline. A 10% higher distance from baseline will be considered significant improvement.
measure: Qaulity of life
time frame: 1 year
description: Improvement in quality of life by Minisota living with Heart Failure Questionnaire. The scale is in points and the higher scale the better. Any improvement in at least 10% from baseline will be considered a significant improvement.
measure: Improvment in the number of hospitalizations for heart failure
time frame: 1 year
description: All hospitalizations for worsening of heart failure will be counted and recorded and the number of hospitalizations for heart failure will be conted in the magnesium compared to the placebo arms.
arm group label: Magnesium
arm group type: Active Comparator
description: oral magnesium oxide tablets [Magnox 520 TM (magnesium oxide monohydrate, 520 mg/day of elemental magnesium), Naveh Pharma, Israel]
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo tablets
intervention type: Drug
intervention name: Placebo Oral Tablet
description: Placebo tablets
arm group label: Placebo
other name: Placebo
intervention type: Drug
intervention name: Magnesium Oxide
description: Magnesium tablets
arm group label: Magnesium
other name: Magnox 520 TM
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Michael Shechter, MD
role: Principal Investigator
affiliation: Sheba Medical Center
last name: Michael Shechter, MD
phone: +97235302617
email: Michael.Shechter@sheba.health.gov.il
last name: Nava Eizenberg, RN
phone: +97235302617
email: Nava.Eizenberg@sheba.health.gov.il
facility: 
status: Recruiting
contact: 
country: Israel
responsible party type: Principal Investigator
investigator affiliation: Sheba Medical Center
investigator full name: Michael Shechter
investigator title: Director, Clinical Research Unit
mesh term: Heart Failure
mesh term: Magnesium Deficiency
mesh term: Magnesium Oxide