xml: <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/NCT06025630</url>
    </required_header>
    <id_info>
      <org_study_id>ERX:2023-063</org_study_id>
      <nct_id>NCT06025630</nct_id>
    </id_info>
    <brief_title>Targeting Endoplasmic Reticulum Stress in Human Hypertension</brief_title>
    <official_title>Targeting Endoplasmic Reticulum Stress in Human Hypertension</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>University of North Texas Health Science Center</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>University of North Texas Health Science Center</source>
    <oversight_info>
      <has_dmc>No</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>
        There is strong evidence suggesting that endoplasmic reticulum stress contributes to&#xD;
        neurogenic and vascular hypertension in various animal models, however this has never been&#xD;
        explored in humans. Therefore, this project will fill this gap by performing a single-blind,&#xD;
        placebo-controlled trial in humans with hypertension.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        The endoplasmic reticulum is a multipurpose organelle found in most human cells, including&#xD;
        those in the brain and the endothelium of blood vessels. One of the primary functions of the&#xD;
        endoplasmic reticulum is the posttranslational folding of new proteins and the reprocessing&#xD;
        of misfolded or damaged proteins. Physiological and pathophysiological conditions can lead to&#xD;
        the accumulation of unfolded/misfolded proteins, thus triggering the unfolded protein&#xD;
        response which is a quality control system that maintains endoplasmic reticulum homeostasis.&#xD;
        However, with prolonged or severe exposure to endoplasmic reticulum stress inducers, the&#xD;
        unfolded protein response can augment the formation of reactive oxygen species, inflammatory&#xD;
        mediators, and transcription factors that trigger sympathetic overactivity and induce&#xD;
        endothelial dysfunction. There is strong evidence suggesting that endoplasmic reticulum&#xD;
        stress contributes to neurogenic and vascular hypertension in various animal models, however&#xD;
        this has never been explored in humans. This proposal builds on prior work in which the&#xD;
        investigators pharmacologically augmented circulating concentrations of the potent&#xD;
        endoplasmic reticulum stress inhibitor, tauroursodeoxycholic acid (TUDCA) and the development&#xD;
        of an assay/test to quantify endoplasmic reticulum stress in cutaneous biopsy samples.&#xD;
  &#xD;
        This study will accomplish the following Specific Aims:&#xD;
  &#xD;
          1. Examine if endoplasmic reticulum stress inhibition, via chronic ingestion of&#xD;
             tauroursodeoxycholic acid, will attenuate 24h blood pressure in humans with elevated&#xD;
             (120-129/&lt;80 mmHg) or stage 1 (130-140/80-90 mmHg) hypertension.&#xD;
  &#xD;
          2. Examine the extent to which endoplasmic reticulum stress inhibition alters neurovascular&#xD;
             control in the participants of Aim 1. Independent of the contribution to blood pressure&#xD;
             regulation, neurovascular function is considered a key risk factor for cardiovascular&#xD;
             morbidity and mortality. As such, the outcome of Aim 2, while providing mechanistic&#xD;
             insight into the blood pressure lowering effect of endoplasmic reticulum stress&#xD;
             inhibition, should be considered independent of the outcomes of Aim 1.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">August 15, 2023</start_date>
    <completion_date type="Anticipated">December 31, 2028</completion_date>
    <primary_completion_date type="Anticipated">December 31, 2028</primary_completion_date>
    <phase>Phase 1/Phase 2</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>This study uses a single-blind, placebo-controlled model.</intervention_model_description>
      <primary_purpose>Basic Science</primary_purpose>
      <masking>Single (Participant)</masking>
      <masking_description>Participants will be blinded to which condition they are randomly assigned (placebo vs TUDCA ingestion)</masking_description>
    </study_design_info>
    <primary_outcome>
      <measure>24 hour Blood Pressure</measure>
      <time_frame>Within 1-2 weeks before and after intervention or placebo</time_frame>
      <description>Systolic and diastolic blood pressure will be measured twice per hour during the day and once per hour at night using a portable cuff.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Neurovascular Function</measure>
      <time_frame>Within 1-2 weeks before and after intervention or placebo</time_frame>
      <description>The microdialysis technique will be used to examine neurovascular function. To do this, blood flow will be measured in response to the local infusion of pharmacological agents that alter blood flow.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Cardiac output</measure>
      <time_frame>Within 1-2 weeks before and after intervention or placebo</time_frame>
      <description>The amount of blood pumped from the heart each minute (i.e., cardiac output) be measured via inert gas (nitrous oxide) rebreathing</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Arterial Pulse Wave Velocity</measure>
      <time_frame>Within 1-2 weeks before and after intervention or placebo</time_frame>
      <description>Resting arterial compliance/stiffness will be assessed by measuring Doppler derived pulse wave velocity.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Endoplasmic Reticulum Stress</measure>
      <time_frame>Within 1-2 weeks before and after intervention or placebo</time_frame>
      <description>Endoplasmic reticulum stress will be quantified by measuring the mRNA expression of spliced X-box binding protein 1 in a cutaneous biopsy sample obtained before and after the intervention.</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">70</enrollment>
    <condition>Hypertension</condition>
    <arm_group>
      <arm_group_label>Endoplasmic Reticulum Stress Inhibition</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
    </arm_group>
    <arm_group>
      <arm_group_label>Placebo</arm_group_label>
      <arm_group_type>Placebo Comparator</arm_group_type>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>TUDCA</intervention_name>
      <description>Endoplasmic reticulum stress will be inhibited by chronic (8 weeks) oral ingestion of the dietary supplement tauroursodeoxycholic acid (TUDCA; 1,750 mg/day)</description>
      <arm_group_label>Endoplasmic Reticulum Stress Inhibition</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Placebo</intervention_name>
      <description>Placebo pills containing microcrystalline cellulose will be ingested over the course of the 8 week intervention.</description>
      <arm_group_label>Placebo</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            1. 18 to 80 years of age&#xD;
  &#xD;
            2. No tobacco/nicotine use within preceding 6 months (e.g., cigarettes, chewing tobacco,&#xD;
               nicotine gum or patches)&#xD;
  &#xD;
            3. Systolic blood pressure &lt;140 mmHg; diastolic blood pressure &lt;90 mmHg (obtained at the&#xD;
               Screening and Familiarization Visit)&#xD;
  &#xD;
            4. Normal 12-lead ECG (obtained at the Screening and Familiarization Visit and reviewed&#xD;
               by a board-certified physician)&#xD;
  &#xD;
            5. Normal clinical results from a medical exam reviewed by a board-certified physician&#xD;
               (e.g., General Health Questionnaire obtained at the Screening and Familiarization&#xD;
               Visit)&#xD;
  &#xD;
            6. Body mass index (BMI) &lt;35 unless athletic/muscular build; calculation = body weight&#xD;
               (kg)/height (m2);&#xD;
  &#xD;
            7. Females only: documentation of a negative pregnancy test prior to the familiarization&#xD;
               and experimental sessions unless post-menopausal&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            1. Not meeting the defined age criteria&#xD;
  &#xD;
            2. Body mass index (BMI) &gt;35 unless athletic/muscular build; calculation = body weight&#xD;
               (kg)/height (m2)&#xD;
  &#xD;
            3. Any tobacco/nicotine use within the last 6 months (e.g., cigarettes, chewing tobacco,&#xD;
               nicotine gum or patches)&#xD;
  &#xD;
            4. Positive pregnancy test&#xD;
  &#xD;
            5. Females with an erratic/irregular menstrual cycle&#xD;
  &#xD;
            6. Females who are breastfeeding&#xD;
  &#xD;
            7. Women who are prescribed a continually releasing hormonal contraceptive (e.g.&#xD;
               NuvaRingTM or other hormone releasing vaginal rings, Depo Provera shot, or birth&#xD;
               control implants such as Nexplanon)&#xD;
  &#xD;
            8. Subjects who weigh less than 80 lbs.&#xD;
  &#xD;
            9. Use of prescription drugs, non-prescription drugs, dietary supplements or herbal&#xD;
               medicines known to alter vascular function unless cleared prior to the study&#xD;
  &#xD;
           10. Use of beta blockers&#xD;
  &#xD;
           11. Daily use of bronchodilators&#xD;
  &#xD;
           12. Use of anti-coagulant therapy&#xD;
  &#xD;
           13. Implanted medical devices (e.g. cardiac pacemaker)&#xD;
  &#xD;
           14. Current or past history of hyperthyroidism, or other thyroid hormone-related disease&#xD;
  &#xD;
           15. Current use of hormone replacement therapy (e.g., estrogen, testosterone)&#xD;
  &#xD;
           16. HbA1c &gt;5.6&#xD;
  &#xD;
           17. Resting systolic blood pressure of &lt;100 mmHg; &gt;140mmHg or diastolic blood pressure&#xD;
               &gt;90mmHg&#xD;
  &#xD;
           18. Abnormal 12-lead ECG or uncontrolled heart rhythm issues causing symptoms, or an&#xD;
               unstable blood pressure&#xD;
  &#xD;
           19. History of cerebrovascular abnormalities (e.g., prior stroke, transient ischemic&#xD;
               attacks, epilepsy)&#xD;
  &#xD;
           20. Known history of atherosclerosis of the carotid arteries (i.e., plaque formation)&#xD;
  &#xD;
           21. History of concussion and or other loss of consciousness within the preceding 30 days&#xD;
  &#xD;
           22. Autonomic dysfunction (e.g., Shy-Drager Syndrome, Bradbury-Eggleston syndrome, sinus&#xD;
               arrhythmia, idiopathic orthostatic hypotension, fainting disorder)&#xD;
  &#xD;
           23. Respiratory illnesses (e.g., chronic asthma (including exercise-induced asthma),&#xD;
               Chronic Obstructive Pulmonary Disease, Reactive Airway Disease)&#xD;
  &#xD;
           24. Any prior history of anaphylaxis, not just prior reactions to the materials used in&#xD;
               this study&#xD;
  &#xD;
           25. Severe phobia of needles&#xD;
  &#xD;
           26. Latex allergy aa) Known allergies or sensitivities to substances used in the study&#xD;
               (e.g., Lidocaine HCL, sodium nitroprusside, acetylcholine, phentolamine, L-NAME,&#xD;
               TUDCA, or related drugs) bb) Donated blood within the last 60 days cc) History or&#xD;
               family history of abnormal blood clotting, clots in deep veins in the legs or pelvis,&#xD;
               or blood clots to the lungs dd) History of alcohol or drug abuse which inhibits the&#xD;
               subject's ability to complete this study ee) Individuals who have had mastectomies ff)&#xD;
               History of methemoglobinemia gg) Current diagnosis of anemia hh) Current Fever (oral&#xD;
               temp &gt;99.5 °F/ 37.5 °C) ii) Current use of PDE3 inhibitors (e.g., Viagra) or soluble&#xD;
               guanylate cyclase (sGC) stimulators (e.g., riociguat), or unwillingness to withhold&#xD;
               medication for 2 weeks prior to laboratory testing jj) Current diagnosis of cancer kk)&#xD;
               Cardiac surgery or cardiac events (e.g., coronary artery bypass graft surgery,&#xD;
               myocardial infarction, heart failure) ll) Diagnosis of neurological disease or&#xD;
               cognitive dysfunction&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>80 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <location>
      <facility>
        <name>University of North Texas Health Science Center</name>
        <address>
          <city>Fort Worth</city>
          <state>Texas</state>
          <zip>76107</zip>
          <country>United States</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Steven A Romero, PhD</last_name>
        <phone>817-735-5159</phone>
        <email>steven.romero@unthsc.edu</email>
      </contact>
      <contact_backup>
        <last_name>Bella Ruiz, BS</last_name>
        <phone>8177352088</phone>
        <email>YsabellaRuiz@my.unthsc.edu</email>
      </contact_backup>
    </location>
    <location_countries>
      <country>United States</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 23, 2023</study_first_submitted>
    <study_first_submitted_qc>August 29, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 6, 2023</study_first_posted>
    <last_update_submitted>August 29, 2023</last_update_submitted>
    <last_update_submitted_qc>August 29, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 6, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>University of North Texas Health Science Center</investigator_affiliation>
      <investigator_full_name>Steven Romero</investigator_full_name>
      <investigator_title>Associate Professor</investigator_title>
    </responsible_party>
    <keyword>high blood pressure</keyword>
    <keyword>tauroursodeoxycholic acid (TUDCA)</keyword>
    <keyword>endoplasmic reticulum</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Hypertension</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06025630
  org study id: ERX:2023-063
  nct id: NCT06025630
  lead sponsor: 
  has dmc: No
  is fda regulated drug: Yes
  is fda regulated device: No
  There is strong evidence suggesting that endoplasmic reticulum stress contributes to
        neurogenic and vascular hypertension in various animal models, however this has never been
        explored in humans. Therefore, this project will fill this gap by performing a single-blind,
        placebo-controlled trial in humans with hypertension.
  The endoplasmic reticulum is a multipurpose organelle found in most human cells, including
        those in the brain and the endothelium of blood vessels. One of the primary functions of the
        endoplasmic reticulum is the posttranslational folding of new proteins and the reprocessing
        of misfolded or damaged proteins. Physiological and pathophysiological conditions can lead to
        the accumulation of unfolded/misfolded proteins, thus triggering the unfolded protein
        response which is a quality control system that maintains endoplasmic reticulum homeostasis.
        However, with prolonged or severe exposure to endoplasmic reticulum stress inducers, the
        unfolded protein response can augment the formation of reactive oxygen species, inflammatory
        mediators, and transcription factors that trigger sympathetic overactivity and induce
        endothelial dysfunction. There is strong evidence suggesting that endoplasmic reticulum
        stress contributes to neurogenic and vascular hypertension in various animal models, however
        this has never been explored in humans. This proposal builds on prior work in which the
        investigators pharmacologically augmented circulating concentrations of the potent
        endoplasmic reticulum stress inhibitor, tauroursodeoxycholic acid (TUDCA) and the development
        of an assay/test to quantify endoplasmic reticulum stress in cutaneous biopsy samples.
  
        This study will accomplish the following Specific Aims:
  
          1. Examine if endoplasmic reticulum stress inhibition, via chronic ingestion of
             tauroursodeoxycholic acid, will attenuate 24h blood pressure in humans with elevated
             (120-129/<80 mmHg) or stage 1 (130-140/80-90 mmHg) hypertension.
  
          2. Examine the extent to which endoplasmic reticulum stress inhibition alters neurovascular
             control in the participants of Aim 1. Independent of the contribution to blood pressure
             regulation, neurovascular function is considered a key risk factor for cardiovascular
             morbidity and mortality. As such, the outcome of Aim 2, while providing mechanistic
             insight into the blood pressure lowering effect of endoplasmic reticulum stress
             inhibition, should be considered independent of the outcomes of Aim 1.
  allocation: Randomized
  intervention model: Parallel Assignment
  intervention model description: This study uses a single-blind, placebo-controlled model.
  primary purpose: Basic Science
  masking: Single (Participant)
  masking description: Participants will be blinded to which condition they are randomly assigned (placebo vs TUDCA ingestion)
  measure: 24 hour Blood Pressure
  time frame: Within 1-2 weeks before and after intervention or placebo
  description: Systolic and diastolic blood pressure will be measured twice per hour during the day and once per hour at night using a portable cuff.
  measure: Neurovascular Function
  time frame: Within 1-2 weeks before and after intervention or placebo
  description: The microdialysis technique will be used to examine neurovascular function. To do this, blood flow will be measured in response to the local infusion of pharmacological agents that alter blood flow.
  measure: Cardiac output
  time frame: Within 1-2 weeks before and after intervention or placebo
  description: The amount of blood pumped from the heart each minute (i.e., cardiac output) be measured via inert gas (nitrous oxide) rebreathing
  measure: Arterial Pulse Wave Velocity
  time frame: Within 1-2 weeks before and after intervention or placebo
  description: Resting arterial compliance/stiffness will be assessed by measuring Doppler derived pulse wave velocity.
  measure: Endoplasmic Reticulum Stress
  time frame: Within 1-2 weeks before and after intervention or placebo
  description: Endoplasmic reticulum stress will be quantified by measuring the mRNA expression of spliced X-box binding protein 1 in a cutaneous biopsy sample obtained before and after the intervention.
  arm group label: Endoplasmic Reticulum Stress Inhibition
  arm group type: Experimental
  arm group label: Placebo
  arm group type: Placebo Comparator
  intervention type: Drug
  intervention name: TUDCA
  description: Endoplasmic reticulum stress will be inhibited by chronic (8 weeks) oral ingestion of the dietary supplement tauroursodeoxycholic acid (TUDCA; 1,750 mg/day)
  arm group label: Endoplasmic Reticulum Stress Inhibition
  intervention type: Drug
  intervention name: Placebo
  description: Placebo pills containing microcrystalline cellulose will be ingested over the course of the 8 week intervention.
  arm group label: Placebo
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 80 Years
  healthy volunteers: No
  facility: 
  status: Recruiting
  contact: 
  contact backup: 
  country: United States
  responsible party type: Principal Investigator
  investigator affiliation: University of North Texas Health Science Center
  investigator full name: Steven Romero
  investigator title: Associate Professor
  mesh term: Hypertension
  sharing ipd: No