<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/NCT02232308</url>
  </required_header>
  <id_info>
    <org_study_id>14-004137</org_study_id>
    <secondary_id>UL1RR024150</secondary_id>
    <secondary_id>P01DK068055</secondary_id>
    <nct_id>NCT02232308</nct_id>
  </id_info>
  <brief_title>Modulation of Heme Oxygenase 1 by Nizatidine and Lisinopril in Healthy Subjects</brief_title>
  <official_title>Modulation of Heme Oxygenase 1 by Nizatidine and Lisinopril in Healthy Subjects</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Adil Bharucha</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Center for Research Resources (NCRR)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Mayo Clinic</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      To assess if oral nizatidine or lisinopril alone and in combination will increase heme&#xD;
      oxygenase 1 (HO-1) protein concentration and activity compared to placebo in healthy&#xD;
      subjects.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Current therapeutic options for gastroparesis are limited to dietary modifications and&#xD;
      pharmacological (i.e., prokinetic and symptomatic) agents. Exciting and novel preliminary&#xD;
      data from our programs demonstrate that (i) reduced expression of heme oxygenase 1 (HO-1) is&#xD;
      responsible for loss of interstitial cells of Cajal and delayed gastric emptying in non-obese&#xD;
      diabetic (NOD) mice, (ii) upregulation of (HO-1) reverses delayed gastric emptying in this&#xD;
      model, perhaps by generating carbon monoxide (CO), which has anti-apoptotic and&#xD;
      cytoprotective actions, and may relax smooth muscle, and (iii) hemin upregulates HO-1 in&#xD;
      humans. However, hemin is exorbitant and can only be administered intravenously. A large&#xD;
      throughput screening assay uncovered that the histamine H2 receptor antagonist nizatidine and&#xD;
      the ACE inhibitor lisinopril upregulate HO-1 in Human Embryonic Kidney (HEK) cells. Hence,&#xD;
      this double-blind placebo-controlled study will randomly assign 24 healthy subjects to one of&#xD;
      4 arms, and HO-1 protein activity and concentration will be assessed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>July 2014</start_date>
  <completion_date type="Actual">September 2014</completion_date>
  <primary_completion_date type="Actual">September 2014</primary_completion_date>
  <phase>Phase 1</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>Basic Science</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in plasma heme oxygenase 1 (HO-1) protein concentration</measure>
    <time_frame>Day 3, Day 10</time_frame>
    <description>Heme oxygenase (HO-1) degrades heme and protects against oxidative stress. HO-1 concentration was measured by a blood test; the units are ng/ml.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Monocyte HO-1 activity</measure>
    <time_frame>Day 3, Day 10</time_frame>
    <description>Heme oxygenase (HO-1) degrades heme and protects against oxidative stress. When HO-1 is induced, more heme is removed, and end products of heme metabolism (i.e., carbon monoxide, iron, and bilirubin) are generated. HO-1 activity was measured by a blood test, the units are pmol bilirubin/mg/h.</description>
  </primary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">24</enrollment>
  <condition>Gastroparesis</condition>
  <arm_group>
    <arm_group_label>Nizatidine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nizatidine (150 mg) will be administered once daily for the first 3 days, then twice daily for days 4-9, and once on day 10.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Lisinopril</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Lisinopril (10 mg) will be administered once daily for the first 3 days, then twice daily for days 4-9, and once on day 10.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Nizatidine plus Lisinopril</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nizatidine (150 mg) and Lisinopril (10 mg) will be administered once daily for the first 3 days, then twice daily for days 4-9, and once on day 10.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo capsules to match active drug will be administered once daily for the first 3 days, then twice daily for days 4-9, and once on day 10.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nizatidine</intervention_name>
    <description>Nizatidine (150 mg) will be administered once daily for the first 3 days, then twice daily for days 4-9, and once on day 10.</description>
    <arm_group_label>Nizatidine</arm_group_label>
    <arm_group_label>Nizatidine plus Lisinopril</arm_group_label>
    <other_name>Axid</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lisinopril</intervention_name>
    <description>Lisinopril (10 mg) will be administered once daily for the first 3 days, then twice daily for days 4-9, and once on day 10.</description>
    <arm_group_label>Lisinopril</arm_group_label>
    <arm_group_label>Nizatidine plus Lisinopril</arm_group_label>
    <other_name>Zestril</other_name>
    <other_name>Prinivil</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Placebo capsules to match active drug will be administered once daily for the first 3 days, then twice daily for days 4-9, and once on day 10.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
          -  Healthy subjects without clinical evidence of significant cardiovascular,&#xD;
             gastrointestinal, hematological, neurological, psychiatric or other disease that may&#xD;
             interfere with the objectives of the study and/or pose safety concerns&#xD;
&#xD;
          -  Normal serum potassium and estimated glomerular filtration rate (eGFR) &gt; 60 ml/minute&#xD;
&#xD;
          -  Baseline systolic BP ≥ 110 mmHg&#xD;
&#xD;
          -  No known hypersensitivity to lisinopril or nizatidine&#xD;
&#xD;
          -  Able to provide written informed consent before participating in the study&#xD;
&#xD;
          -  Able to communicate adequately with the investigator and to comply with the&#xD;
             requirements for the entire study.&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          -  Pregnant&#xD;
&#xD;
          -  Breast feeding&#xD;
&#xD;
          -  Current smoker&#xD;
&#xD;
          -  Symptoms of functional GI disorder as assessed by a validated questionnaire&#xD;
&#xD;
          -  Previous history of peptic ulcer disease.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Adil Bharucha, MBBS, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Mayo Clinic</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Mayo Clinic in Rochester</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2015</verification_date>
  <study_first_submitted>June 23, 2014</study_first_submitted>
  <study_first_submitted_qc>September 2, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 5, 2014</study_first_posted>
  <last_update_submitted>April 28, 2015</last_update_submitted>
  <last_update_submitted_qc>April 28, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">April 30, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Mayo Clinic</investigator_affiliation>
    <investigator_full_name>Adil Bharucha</investigator_full_name>
    <investigator_title>Professor of Medicine</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Gastroparesis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lisinopril</mesh_term>
    <mesh_term>Nizatidine</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/NCT02232308
org study id: 14-004137
secondary id: UL1RR024150
secondary id: P01DK068055
nct id: NCT02232308
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
To assess if oral nizatidine or lisinopril alone and in combination will increase heme
      oxygenase 1 (HO-1) protein concentration and activity compared to placebo in healthy
      subjects.
Current therapeutic options for gastroparesis are limited to dietary modifications and
      pharmacological (i.e., prokinetic and symptomatic) agents. Exciting and novel preliminary
      data from our programs demonstrate that (i) reduced expression of heme oxygenase 1 (HO-1) is
      responsible for loss of interstitial cells of Cajal and delayed gastric emptying in non-obese
      diabetic (NOD) mice, (ii) upregulation of (HO-1) reverses delayed gastric emptying in this
      model, perhaps by generating carbon monoxide (CO), which has anti-apoptotic and
      cytoprotective actions, and may relax smooth muscle, and (iii) hemin upregulates HO-1 in
      humans. However, hemin is exorbitant and can only be administered intravenously. A large
      throughput screening assay uncovered that the histamine H2 receptor antagonist nizatidine and
      the ACE inhibitor lisinopril upregulate HO-1 in Human Embryonic Kidney (HEK) cells. Hence,
      this double-blind placebo-controlled study will randomly assign 24 healthy subjects to one of
      4 arms, and HO-1 protein activity and concentration will be assessed.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: Double (Participant, Investigator)
measure: Change in plasma heme oxygenase 1 (HO-1) protein concentration
time frame: Day 3, Day 10
description: Heme oxygenase (HO-1) degrades heme and protects against oxidative stress. HO-1 concentration was measured by a blood test; the units are ng/ml.
measure: Change in Monocyte HO-1 activity
time frame: Day 3, Day 10
description: Heme oxygenase (HO-1) degrades heme and protects against oxidative stress. When HO-1 is induced, more heme is removed, and end products of heme metabolism (i.e., carbon monoxide, iron, and bilirubin) are generated. HO-1 activity was measured by a blood test, the units are pmol bilirubin/mg/h.
arm group label: Nizatidine
arm group type: Experimental
description: Nizatidine (150 mg) will be administered once daily for the first 3 days, then twice daily for days 4-9, and once on day 10.
arm group label: Lisinopril
arm group type: Experimental
description: Lisinopril (10 mg) will be administered once daily for the first 3 days, then twice daily for days 4-9, and once on day 10.
arm group label: Nizatidine plus Lisinopril
arm group type: Experimental
description: Nizatidine (150 mg) and Lisinopril (10 mg) will be administered once daily for the first 3 days, then twice daily for days 4-9, and once on day 10.
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo capsules to match active drug will be administered once daily for the first 3 days, then twice daily for days 4-9, and once on day 10.
intervention type: Drug
intervention name: Nizatidine
description: Nizatidine (150 mg) will be administered once daily for the first 3 days, then twice daily for days 4-9, and once on day 10.
arm group label: Nizatidine
arm group label: Nizatidine plus Lisinopril
other name: Axid
intervention type: Drug
intervention name: Lisinopril
description: Lisinopril (10 mg) will be administered once daily for the first 3 days, then twice daily for days 4-9, and once on day 10.
arm group label: Lisinopril
arm group label: Nizatidine plus Lisinopril
other name: Zestril
other name: Prinivil
intervention type: Drug
intervention name: Placebo
description: Placebo capsules to match active drug will be administered once daily for the first 3 days, then twice daily for days 4-9, and once on day 10.
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Adil Bharucha, MBBS, MD
role: Principal Investigator
affiliation: Mayo Clinic
facility: 
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: Mayo Clinic
investigator full name: Adil Bharucha
investigator title: Professor of Medicine
mesh term: Gastroparesis
mesh term: Lisinopril
mesh term: Nizatidine