<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/NCT03812380</url>
  </required_header>
  <id_info>
    <org_study_id>STU 042018-078</org_study_id>
    <nct_id>NCT03812380</nct_id>
  </id_info>
  <brief_title>Averting Complications of Proton Pump Inhibitor Therapy by Effervescent Calcium Magnesium Citrate</brief_title>
  <official_title>Averting Complications of Proton Pump Inhibitor Therapy by Effervescent Calcium Magnesium Citrate</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Texas Southwestern Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Texas Southwestern Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Proton pump inhibitors (PPIs) are widely used for the control of gastric ulcer-gastritis,&#xD;
      erosive esophagitis (gastroesophageal reflux disease), peptic ulcer disease (duodenal ulcer),&#xD;
      and heartburn. Despite their efficacy, their use has been implicated in possibly causing&#xD;
      fragility fractures (osteoporosis), hypomagnesemia (magnesium deficiency) and increased risk&#xD;
      of chronic kidney disease (CKD). The current trial represents the investigators' ongoing&#xD;
      effort to discern whether these complications could be averted by effervescent calcium&#xD;
      magnesium citrate (EffCaMgCit).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In a single-dose bioavailability study, the investigators showed previously that provision of&#xD;
      calcium and magnesium in a soluble form as EffCaMgCit improved intestinal absorption of&#xD;
      calcium and magnesium and suppressed parathyroid function during PPI treatment, compared with&#xD;
      calcium carbonate. In a multidosing trial with esomeprazole 40 mg/day for 28 days, EffCaMgCit&#xD;
      suppressed parathyroid function and bone turnover, and increased serum and urinary magnesium,&#xD;
      compared with placebo. Moreover, EffCaMgCit co-administered with PPI conferred an alkali&#xD;
      load, and averted apparent acid load conferred by PPI (when given with placebo).&#xD;
&#xD;
      In the current proposal, the investigators wish to conduct a 2-year treatment trial, directed&#xD;
      at obtaining more definitive evidence that EffCaMgCit overcomes all three complications of&#xD;
      PPI.&#xD;
&#xD;
      Aim 1. To test the hypothesis that EffCaMgCit would prevent/treat osteoporosis, by&#xD;
      suppressing parathyroid function and bone resorption, thereby stabilizing bone mineral&#xD;
      density (BMD). The critical endpoint will be BMD. Secondary endpoints will be serum PTH and&#xD;
      C-terminal telopeptide (CTX).&#xD;
&#xD;
      Aim 2. To test the hypothesis that EffCaMgCit would prevent/treat hypomagnesemia/magnesium&#xD;
      deficiency, by providing bioavailable magnesium. The critical endpoint will be fractional&#xD;
      excretion of magnesium (FEMg) and free muscle magnesium by MRS. Secondary endpoints will be&#xD;
      serum and urinary magnesium.&#xD;
&#xD;
      Aim 3. To test the hypothesis that EffCaMgCit would reduce the risk of CKD during PPI use by&#xD;
      averting putative hypomagnesemia/magnesium deficiency and neutralizing acid load. The&#xD;
      investigators propose that PPI causes hypomagnesemia/magnesium deficiency and confers an acid&#xD;
      load, - factors implicated for incident CKD and its progression. EffCaMgCit is expected to&#xD;
      avert incident CKD by providing bioavailable magnesium and alkali load. Critical endpoints&#xD;
      will be endogenous creatinine clearance, FEMg, free muscle magnesium and acid-base status.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    The study was terminated due to a severe decrease in enrollment over the years 2020 and 2021.&#xD;
    The major obstacle which hindered participation of subjects was the COVID-19 pandemic. Research&#xD;
    was halted. Remaining study patients were withdrawn.&#xD;
  </why_stopped>
  <start_date type="Actual">January 1, 2019</start_date>
  <completion_date type="Actual">August 11, 2021</completion_date>
  <primary_completion_date type="Actual">August 11, 2021</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>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>To provide adequate blinding, each medication sachet will be labelled with the study name, IRB number, principal investigator's name, expiration date and identification number of the study subject. Labels will be applied to the appropriate medication sachets once the subject has been randomized and assigned to a treatment group. Labelling of the sachets will be done by personnel who are not engaged in patient care.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change From Baseline in Bone Mineral Density (BMD) T-Score at 2 Years</measure>
    <time_frame>Baseline and 2 years</time_frame>
    <description>Change from baseline in bone mineral density (BMD) T-Score at 2 years as measured by dual photon absorptiometry. The range, as defined by the World Health Organization (WHO), for T-Score is: -1 and above = Normal, Between -1 and -2.5 = Osteopenia, -2.5 and below = osteoporosis.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change From Baseline in Bone Mineral Density (BMD) Z-Score at 2 Years</measure>
    <time_frame>Baseline and 2 years</time_frame>
    <description>Change from baseline in bone mineral density (BMD) Z-score at 2 years as measured by dual photon absorptiometry. Outcome is considered positive if the Z Score after two years of treatment becomes less negative (less than -2). There is no specific score range for the Z Score.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change From Baseline in the Fractional Excretion of Magnesium (FEMg) at 2 Years</measure>
    <time_frame>Baseline and 2 years</time_frame>
    <description>Change from baseline in the fractional excretion of magnesium (FEMg) at 2 years as measured by the ratio of magnesium clearance and creatinine clearance, using 24-h urinary magnesium and creatinine and corresponding serum magnesium and creatinine obtained post meal/load.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change From Baseline in Free Muscle Magnesium at 2 Years</measure>
    <time_frame>Baseline and 2 years</time_frame>
    <description>Change From baseline in free muscle magnesium at 2 years as assessed by measuring intracellular Mg in a calf muscle, by using 31P (Phosphorous) magnetic resonance spectroscopy (MRS).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change From Baseline in Endogenous Creatinine Clearance at 2 Years</measure>
    <time_frame>Baseline and 2 years</time_frame>
    <description>Change from baseline in endogenous creatinine clearance at 2 years will be measured. Endogenous creatinine clearance will be obtained by using 24-h urinary creatinine and post-meal/load venous blood sample ((uCr, mg/24hr) / (sCr,mg/dL * 14.4))</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Serum Parathyroid Function (PTH) at 2 Years</measure>
    <time_frame>Baseline and 2 years</time_frame>
    <description>Change from baseline in serum parathyroid function (PTH) at 2 years will be measured by Biomerica Intact-PTH ELISA.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Serum Bone Resorption Marker C-terminal Telopeptide (CTX) at 2 Years</measure>
    <time_frame>Baseline and 2 years</time_frame>
    <description>Change from baseline in serum bone resorption marker C-terminal telopeptide (CTX) at 2 years will be measured by lab finding utilizing ELISA CTX-I (CrossLaps).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Serum Magnesium at 2 Years</measure>
    <time_frame>Baseline and 2 years</time_frame>
    <description>Change from baseline in serum magnesium at 2 years will be measured by ion selective electrode.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Urine Magnesium at 2 Years</measure>
    <time_frame>Baseline and 2 years</time_frame>
    <description>Change from baseline in urine magnesium at 2 years was measured by by atomic absorption.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Serum Bicarbonate at 2 Years</measure>
    <time_frame>Baseline and 2 years</time_frame>
    <description>Change from baseline in serum bicarbonate at 2 years will be measured to see improvement in acid based status in lowering kidney function impairment.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">62</enrollment>
  <condition>Osteoporosis</condition>
  <condition>Hypomagnesemia</condition>
  <arm_group>
    <arm_group_label>EffCaMgCit</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate; designed to be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. Each sachet of EffCaMgCit will contain 400 units of vitamin D.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>EffCaMgCit</intervention_name>
    <description>Each sachet of EffCaMgCit will contain 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate.</description>
    <arm_group_label>EffCaMgCit</arm_group_label>
    <other_name>Effervescent calcium magnesium citrate</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Must have taken PPI (omeprazole or equivalent ≥ 20 mg/day, ≥ three times per week, for&#xD;
             at least 2 months)&#xD;
&#xD;
          -  Expected to continue at a similar dosage&#xD;
&#xD;
          -  Stage 1 hypertension (with systolic blood pressure &lt;140 and diastolic &lt;90)&#xD;
&#xD;
          -  controlled diabetes mellitus Type II with HbA1C less than 7%&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  end-stage renal failure on dialysis&#xD;
&#xD;
          -  hypercalcemia&#xD;
&#xD;
          -  hypophosphatemia (serum P &lt; 2.5 mg/dL)&#xD;
&#xD;
          -  hypertension stage 2 or higher&#xD;
&#xD;
          -  diabetes Type II with HbA1C ≥ 7%&#xD;
&#xD;
          -  treatment with adrenocorticosteroids, diuretics, non-steroidal anti-inflammatory&#xD;
             agents&#xD;
&#xD;
          -  regular dose of magnesium supplements, bisphosphonate, teriparatide, denosumab or&#xD;
             selective estrogen receptor modulators.&#xD;
&#xD;
        Inclusion/exclusion of other drugs or conditions will be considered on an individual basis.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Khashayar Sakhaee, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>UTSW</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Texas Southwestern Medical Center</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75390</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2022</verification_date>
  <study_first_submitted>May 24, 2018</study_first_submitted>
  <study_first_submitted_qc>January 17, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 23, 2019</study_first_posted>
  <results_first_submitted>July 20, 2022</results_first_submitted>
  <results_first_submitted_qc>July 20, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">August 17, 2022</results_first_posted>
  <last_update_submitted>July 20, 2022</last_update_submitted>
  <last_update_submitted_qc>July 20, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 17, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Texas Southwestern Medical Center</investigator_affiliation>
    <investigator_full_name>Khashayar Sakhaee</investigator_full_name>
    <investigator_title>Chief, Division of Mineral Metabolism; Professor, Internal Medicine</investigator_title>
  </responsible_party>
  <keyword>Bone mineral density</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Osteoporosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Magnesium citrate</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>September 1, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/80/NCT03812380/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>Out of the 62 participants enrolled, only 44 met the inclusion criteria and were randomized to the treatment.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>EffCaMgCit</title>
          <description>19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate; designed to be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. Each sachet of EffCaMgCit will contain 400 units of vitamin D.&#xD;
EffCaMgCit: Each sachet of EffCaMgCit will contain 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate.</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.&#xD;
Placebo: Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="22"/>
                <participants group_id="P2" count="22"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="22"/>
                <participants group_id="P2" count="21"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="4"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Early termination of study</title>
              <participants_list>
                <participants group_id="P1" count="14"/>
                <participants group_id="P2" count="14"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>EffCaMgCit</title>
          <description>19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate; designed to be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. Each sachet of EffCaMgCit will contain 400 units of vitamin D.&#xD;
EffCaMgCit: Each sachet of EffCaMgCit will contain 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate.</description>
        </group>
        <group group_id="B2">
          <title>Placebo</title>
          <description>Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.&#xD;
Placebo: Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="22"/>
            <count group_id="B2" value="22"/>
            <count group_id="B3" value="44"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="16"/>
                    <measurement group_id="B3" value="28"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="27"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="22"/>
                    <measurement group_id="B2" value="21"/>
                    <measurement group_id="B3" value="43"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="21"/>
                    <measurement group_id="B3" value="41"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="22"/>
                    <measurement group_id="B2" value="22"/>
                    <measurement group_id="B3" value="44"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change From Baseline in Bone Mineral Density (BMD) T-Score at 2 Years</title>
        <description>Change from baseline in bone mineral density (BMD) T-Score at 2 years as measured by dual photon absorptiometry. The range, as defined by the World Health Organization (WHO), for T-Score is: -1 and above = Normal, Between -1 and -2.5 = Osteopenia, -2.5 and below = osteoporosis.</description>
        <time_frame>Baseline and 2 years</time_frame>
        <population>Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here.</population>
        <group_list>
          <group group_id="O1">
            <title>EffCaMgCit</title>
            <description>19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate; designed to be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. Each sachet of EffCaMgCit will contain 400 units of vitamin D.&#xD;
EffCaMgCit: Each sachet of EffCaMgCit will contain 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.&#xD;
Placebo: Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Bone Mineral Density (BMD) T-Score at 2 Years</title>
          <description>Change from baseline in bone mineral density (BMD) T-Score at 2 years as measured by dual photon absorptiometry. The range, as defined by the World Health Organization (WHO), for T-Score is: -1 and above = Normal, Between -1 and -2.5 = Osteopenia, -2.5 and below = osteoporosis.</description>
          <population>Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here.</population>
          <units>T-Score</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>L2-L4 T-Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="-0.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Femoral Neck T-Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="-1.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Total Hip T-Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="-0.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Radial 1/3rd T-Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="-0.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Change From Baseline in Bone Mineral Density (BMD) Z-Score at 2 Years</title>
        <description>Change from baseline in bone mineral density (BMD) Z-score at 2 years as measured by dual photon absorptiometry. Outcome is considered positive if the Z Score after two years of treatment becomes less negative (less than -2). There is no specific score range for the Z Score.</description>
        <time_frame>Baseline and 2 years</time_frame>
        <population>Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here.</population>
        <group_list>
          <group group_id="O1">
            <title>EffCaMgCit</title>
            <description>19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate; designed to be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. Each sachet of EffCaMgCit will contain 400 units of vitamin D.&#xD;
EffCaMgCit: Each sachet of EffCaMgCit will contain 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.&#xD;
Placebo: Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Bone Mineral Density (BMD) Z-Score at 2 Years</title>
          <description>Change from baseline in bone mineral density (BMD) Z-score at 2 years as measured by dual photon absorptiometry. Outcome is considered positive if the Z Score after two years of treatment becomes less negative (less than -2). There is no specific score range for the Z Score.</description>
          <population>Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here.</population>
          <units>Z-Score</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>L2L4 Z-Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="-0.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Femoral Neck Z-Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="-0.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Total Hip Z-Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="-0.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Radial 1/3rd Z-Score</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="-0.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Change From Baseline in the Fractional Excretion of Magnesium (FEMg) at 2 Years</title>
        <description>Change from baseline in the fractional excretion of magnesium (FEMg) at 2 years as measured by the ratio of magnesium clearance and creatinine clearance, using 24-h urinary magnesium and creatinine and corresponding serum magnesium and creatinine obtained post meal/load.</description>
        <time_frame>Baseline and 2 years</time_frame>
        <population>Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here.</population>
        <group_list>
          <group group_id="O1">
            <title>EffCaMgCit</title>
            <description>19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate; designed to be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. Each sachet of EffCaMgCit will contain 400 units of vitamin D.&#xD;
EffCaMgCit: Each sachet of EffCaMgCit will contain 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.&#xD;
Placebo: Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in the Fractional Excretion of Magnesium (FEMg) at 2 Years</title>
          <description>Change from baseline in the fractional excretion of magnesium (FEMg) at 2 years as measured by the ratio of magnesium clearance and creatinine clearance, using 24-h urinary magnesium and creatinine and corresponding serum magnesium and creatinine obtained post meal/load.</description>
          <population>Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here.</population>
          <units>percentage</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="-1.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Change From Baseline in Free Muscle Magnesium at 2 Years</title>
        <description>Change From baseline in free muscle magnesium at 2 years as assessed by measuring intracellular Mg in a calf muscle, by using 31P (Phosphorous) magnetic resonance spectroscopy (MRS).</description>
        <time_frame>Baseline and 2 years</time_frame>
        <population>Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here.</population>
        <group_list>
          <group group_id="O1">
            <title>EffCaMgCit</title>
            <description>19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate; designed to be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. Each sachet of EffCaMgCit will contain 400 units of vitamin D.&#xD;
EffCaMgCit: Each sachet of EffCaMgCit will contain 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.&#xD;
Placebo: Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Free Muscle Magnesium at 2 Years</title>
          <description>Change From baseline in free muscle magnesium at 2 years as assessed by measuring intracellular Mg in a calf muscle, by using 31P (Phosphorous) magnetic resonance spectroscopy (MRS).</description>
          <population>Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here.</population>
          <units>mmol/L</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="-0.044"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Change From Baseline in Endogenous Creatinine Clearance at 2 Years</title>
        <description>Change from baseline in endogenous creatinine clearance at 2 years will be measured. Endogenous creatinine clearance will be obtained by using 24-h urinary creatinine and post-meal/load venous blood sample ((uCr, mg/24hr) / (sCr,mg/dL * 14.4))</description>
        <time_frame>Baseline and 2 years</time_frame>
        <population>Because of severe decrease in enrolled participants due to COVID-19 restrictions and consequently a suspension of research activities resulted in the early termination of this study. Only 1 subject completed the 2 year timepoint for which the data is summarized here.</population>
        <group_list>
          <group group_id="O1">
            <title>EffCaMgCit</title>
            <description>19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate; designed to be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. Each sachet of EffCaMgCit will contain 400 units of vitamin D.&#xD;
EffCaMgCit: Each sachet of EffCaMgCit will contain 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.&#xD;
Placebo: Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Endogenous Creatinine Clearance at 2 Years</title>
          <description>Change from baseline in endogenous creatinine clearance at 2 years will be measured. Endogenous creatinine clearance will be obtained by using 24-h urinary creatinine and post-meal/load venous blood sample ((uCr, mg/24hr) / (sCr,mg/dL * 14.4))</description>
          <population>Because of severe decrease in enrolled participants due to COVID-19 restrictions and consequently a suspension of research activities resulted in the early termination of this study. Only 1 subject completed the 2 year timepoint for which the data is summarized here.</population>
          <units>ml/min</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Serum Parathyroid Function (PTH) at 2 Years</title>
        <description>Change from baseline in serum parathyroid function (PTH) at 2 years will be measured by Biomerica Intact-PTH ELISA.</description>
        <time_frame>Baseline and 2 years</time_frame>
        <population>Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here.</population>
        <group_list>
          <group group_id="O1">
            <title>EffCaMgCit</title>
            <description>19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate; designed to be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. Each sachet of EffCaMgCit will contain 400 units of vitamin D.&#xD;
EffCaMgCit: Each sachet of EffCaMgCit will contain 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.&#xD;
Placebo: Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Serum Parathyroid Function (PTH) at 2 Years</title>
          <description>Change from baseline in serum parathyroid function (PTH) at 2 years will be measured by Biomerica Intact-PTH ELISA.</description>
          <population>Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here.</population>
          <units>pg/ml</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="75"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Serum Bone Resorption Marker C-terminal Telopeptide (CTX) at 2 Years</title>
        <description>Change from baseline in serum bone resorption marker C-terminal telopeptide (CTX) at 2 years will be measured by lab finding utilizing ELISA CTX-I (CrossLaps).</description>
        <time_frame>Baseline and 2 years</time_frame>
        <population>Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here.</population>
        <group_list>
          <group group_id="O1">
            <title>EffCaMgCit</title>
            <description>19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate; designed to be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. Each sachet of EffCaMgCit will contain 400 units of vitamin D.&#xD;
EffCaMgCit: Each sachet of EffCaMgCit will contain 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.&#xD;
Placebo: Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Serum Bone Resorption Marker C-terminal Telopeptide (CTX) at 2 Years</title>
          <description>Change from baseline in serum bone resorption marker C-terminal telopeptide (CTX) at 2 years will be measured by lab finding utilizing ELISA CTX-I (CrossLaps).</description>
          <population>Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here.</population>
          <units>ng/ml</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="0.15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Serum Magnesium at 2 Years</title>
        <description>Change from baseline in serum magnesium at 2 years will be measured by ion selective electrode.</description>
        <time_frame>Baseline and 2 years</time_frame>
        <population>Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here.</population>
        <group_list>
          <group group_id="O1">
            <title>EffCaMgCit</title>
            <description>19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate; designed to be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. Each sachet of EffCaMgCit will contain 400 units of vitamin D.&#xD;
EffCaMgCit: Each sachet of EffCaMgCit will contain 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.&#xD;
Placebo: Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Serum Magnesium at 2 Years</title>
          <description>Change from baseline in serum magnesium at 2 years will be measured by ion selective electrode.</description>
          <population>Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here.</population>
          <units>mg/dL</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="0.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Urine Magnesium at 2 Years</title>
        <description>Change from baseline in urine magnesium at 2 years was measured by by atomic absorption.</description>
        <time_frame>Baseline and 2 years</time_frame>
        <population>Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here.</population>
        <group_list>
          <group group_id="O1">
            <title>EffCaMgCit</title>
            <description>19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate; designed to be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. Each sachet of EffCaMgCit will contain 400 units of vitamin D.&#xD;
EffCaMgCit: Each sachet of EffCaMgCit will contain 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.&#xD;
Placebo: Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Urine Magnesium at 2 Years</title>
          <description>Change from baseline in urine magnesium at 2 years was measured by by atomic absorption.</description>
          <population>Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here.</population>
          <units>mg/day</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="-8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Serum Bicarbonate at 2 Years</title>
        <description>Change from baseline in serum bicarbonate at 2 years will be measured to see improvement in acid based status in lowering kidney function impairment.</description>
        <time_frame>Baseline and 2 years</time_frame>
        <population>Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here.</population>
        <group_list>
          <group group_id="O1">
            <title>EffCaMgCit</title>
            <description>19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate; designed to be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. Each sachet of EffCaMgCit will contain 400 units of vitamin D.&#xD;
EffCaMgCit: Each sachet of EffCaMgCit will contain 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate.</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.&#xD;
Placebo: Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Serum Bicarbonate at 2 Years</title>
          <description>Change from baseline in serum bicarbonate at 2 years will be measured to see improvement in acid based status in lowering kidney function impairment.</description>
          <population>Because of severe enrollment difficulty due to COVID-19 restrictions and consequently a suspension of research activities, this study was terminated early. Only one subject completed the full two year duration for which data are summarized here.</population>
          <units>mmol/L</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="-2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From the participant's first dose at baseline (0 month) to the end of 24 months</time_frame>
      <desc>A severe decrease in the enrolled participants due to COVID restrictions and consequently a suspension of research activities resulted in the early termination of this study.</desc>
      <group_list>
        <group group_id="E1">
          <title>EffCaMgCit</title>
          <description>19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate; designed to be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. Each sachet of EffCaMgCit will contain 400 units of vitamin D.&#xD;
EffCaMgCit: Each sachet of EffCaMgCit will contain 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate.</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.&#xD;
Placebo: Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Gas, smelly gas and bloating</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="22"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Khashayar Sakhaee, MD</name_or_title>
      <organization>UT Southwestern Medical Center</organization>
      <phone>214-648-0324</phone>
      <email>Khashayar.Sakhaee@UTSouthwestern.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03812380
org study id: STU 042018-078
nct id: NCT03812380
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Proton pump inhibitors (PPIs) are widely used for the control of gastric ulcer-gastritis,
      erosive esophagitis (gastroesophageal reflux disease), peptic ulcer disease (duodenal ulcer),
      and heartburn. Despite their efficacy, their use has been implicated in possibly causing
      fragility fractures (osteoporosis), hypomagnesemia (magnesium deficiency) and increased risk
      of chronic kidney disease (CKD). The current trial represents the investigators' ongoing
      effort to discern whether these complications could be averted by effervescent calcium
      magnesium citrate (EffCaMgCit).
In a single-dose bioavailability study, the investigators showed previously that provision of
      calcium and magnesium in a soluble form as EffCaMgCit improved intestinal absorption of
      calcium and magnesium and suppressed parathyroid function during PPI treatment, compared with
      calcium carbonate. In a multidosing trial with esomeprazole 40 mg/day for 28 days, EffCaMgCit
      suppressed parathyroid function and bone turnover, and increased serum and urinary magnesium,
      compared with placebo. Moreover, EffCaMgCit co-administered with PPI conferred an alkali
      load, and averted apparent acid load conferred by PPI (when given with placebo).

      In the current proposal, the investigators wish to conduct a 2-year treatment trial, directed
      at obtaining more definitive evidence that EffCaMgCit overcomes all three complications of
      PPI.

      Aim 1. To test the hypothesis that EffCaMgCit would prevent/treat osteoporosis, by
      suppressing parathyroid function and bone resorption, thereby stabilizing bone mineral
      density (BMD). The critical endpoint will be BMD. Secondary endpoints will be serum PTH and
      C-terminal telopeptide (CTX).

      Aim 2. To test the hypothesis that EffCaMgCit would prevent/treat hypomagnesemia/magnesium
      deficiency, by providing bioavailable magnesium. The critical endpoint will be fractional
      excretion of magnesium (FEMg) and free muscle magnesium by MRS. Secondary endpoints will be
      serum and urinary magnesium.

      Aim 3. To test the hypothesis that EffCaMgCit would reduce the risk of CKD during PPI use by
      averting putative hypomagnesemia/magnesium deficiency and neutralizing acid load. The
      investigators propose that PPI causes hypomagnesemia/magnesium deficiency and confers an acid
      load, - factors implicated for incident CKD and its progression. EffCaMgCit is expected to
      avert incident CKD by providing bioavailable magnesium and alkali load. Critical endpoints
      will be endogenous creatinine clearance, FEMg, free muscle magnesium and acid-base status.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: To provide adequate blinding, each medication sachet will be labelled with the study name, IRB number, principal investigator's name, expiration date and identification number of the study subject. Labels will be applied to the appropriate medication sachets once the subject has been randomized and assigned to a treatment group. Labelling of the sachets will be done by personnel who are not engaged in patient care.
measure: Change From Baseline in Bone Mineral Density (BMD) T-Score at 2 Years
time frame: Baseline and 2 years
description: Change from baseline in bone mineral density (BMD) T-Score at 2 years as measured by dual photon absorptiometry. The range, as defined by the World Health Organization (WHO), for T-Score is: -1 and above = Normal, Between -1 and -2.5 = Osteopenia, -2.5 and below = osteoporosis.
measure: Change From Baseline in Bone Mineral Density (BMD) Z-Score at 2 Years
time frame: Baseline and 2 years
description: Change from baseline in bone mineral density (BMD) Z-score at 2 years as measured by dual photon absorptiometry. Outcome is considered positive if the Z Score after two years of treatment becomes less negative (less than -2). There is no specific score range for the Z Score.
measure: Change From Baseline in the Fractional Excretion of Magnesium (FEMg) at 2 Years
time frame: Baseline and 2 years
description: Change from baseline in the fractional excretion of magnesium (FEMg) at 2 years as measured by the ratio of magnesium clearance and creatinine clearance, using 24-h urinary magnesium and creatinine and corresponding serum magnesium and creatinine obtained post meal/load.
measure: Change From Baseline in Free Muscle Magnesium at 2 Years
time frame: Baseline and 2 years
description: Change From baseline in free muscle magnesium at 2 years as assessed by measuring intracellular Mg in a calf muscle, by using 31P (Phosphorous) magnetic resonance spectroscopy (MRS).
measure: Change From Baseline in Endogenous Creatinine Clearance at 2 Years
time frame: Baseline and 2 years
description: Change from baseline in endogenous creatinine clearance at 2 years will be measured. Endogenous creatinine clearance will be obtained by using 24-h urinary creatinine and post-meal/load venous blood sample ((uCr, mg/24hr) / (sCr,mg/dL * 14.4))
measure: Change From Baseline in Serum Parathyroid Function (PTH) at 2 Years
time frame: Baseline and 2 years
description: Change from baseline in serum parathyroid function (PTH) at 2 years will be measured by Biomerica Intact-PTH ELISA.
measure: Change From Baseline in Serum Bone Resorption Marker C-terminal Telopeptide (CTX) at 2 Years
time frame: Baseline and 2 years
description: Change from baseline in serum bone resorption marker C-terminal telopeptide (CTX) at 2 years will be measured by lab finding utilizing ELISA CTX-I (CrossLaps).
measure: Change From Baseline in Serum Magnesium at 2 Years
time frame: Baseline and 2 years
description: Change from baseline in serum magnesium at 2 years will be measured by ion selective electrode.
measure: Change From Baseline in Urine Magnesium at 2 Years
time frame: Baseline and 2 years
description: Change from baseline in urine magnesium at 2 years was measured by by atomic absorption.
measure: Change From Baseline in Serum Bicarbonate at 2 Years
time frame: Baseline and 2 years
description: Change from baseline in serum bicarbonate at 2 years will be measured to see improvement in acid based status in lowering kidney function impairment.
arm group label: EffCaMgCit
arm group type: Experimental
description: 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate; designed to be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. Each sachet of EffCaMgCit will contain 400 units of vitamin D.
arm group label: Placebo
arm group type: Placebo Comparator
description: Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.
intervention type: Drug
intervention name: EffCaMgCit
description: Each sachet of EffCaMgCit will contain 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate.
arm group label: EffCaMgCit
other name: Effervescent calcium magnesium citrate
intervention type: Other
intervention name: Placebo
description: Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.
arm group label: Placebo
criteria: 
gender: All
minimum age: 21 Years
maximum age: 99 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Khashayar Sakhaee, MD
role: Principal Investigator
affiliation: UTSW
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Texas Southwestern Medical Center
investigator full name: Khashayar Sakhaee
investigator title: Chief, Division of Mineral Metabolism; Professor, Internal Medicine
mesh term: Osteoporosis
mesh term: Magnesium citrate
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 