<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/NCT03234361</url>
  </required_header>
  <id_info>
    <org_study_id>STU 012017-052</org_study_id>
    <nct_id>NCT03234361</nct_id>
  </id_info>
  <brief_title>Preventing Hypertension and Sympathetic Overactivation by Targeting Phosphate</brief_title>
  <official_title>Preventing Hypertension and Sympathetic Overactivation by Targeting Phosphate</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>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      An increasing number of studies have indicated that most fast food and common grocery items,&#xD;
      contain large amount of inorganic phosphate-based food additives , which are highly&#xD;
      absorbable. The long-term cardiovascular consequences of a high phosphate diet are unknown&#xD;
      but the existing database implicates phosphate excess as an independent risk factor for&#xD;
      cardiovascular events in individuals with and without chronic kidney diseases (CKD). High&#xD;
      phosphate consumption clearly induces BP elevation in rats with normal kidneys. However, the&#xD;
      mechanisms underlying phosphate-induced hypertension and the relevance of these rodent&#xD;
      studies to human hypertension have not been determined. We seek to investigate the role of&#xD;
      high phosphate diet in human hypertension and assess the effect of high phosphate diet on&#xD;
      muscle sympathetic nerve activity and the exercise pressor reflex.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Animal studies suggest that high phosphate diet raises blood pressure but the mechanism&#xD;
      underlying this phenomenon is not known. To study the effect of high phosphorus diet on blood&#xD;
      pressure in humans, we will perform randomized crossover studies in stage 1 prehypertensive&#xD;
      subjects. To ensure stable Pi intake prior to randomization, Pi consumption will be estimated&#xD;
      by food recall during a run-in and washout phase for 2 consecutive days, using the Automated&#xD;
      Self-Administered 24-Hour (ASA24®) Dietary Assessment Tool&#xD;
      (https://epi.grants.cancer.gov/asa24/). After the run-in period, all subjects will be&#xD;
      maintained on a low Pi diet (700 mg/d) and a low Na diet of approximately 1,930 mg/d&#xD;
      throughout the study for 8 weeks. Subjects will also be randomized to receive Sodium&#xD;
      Phosphate 2 capsules daily (containing a total of 500 mg of Pi, 372mg of sodium) for 4 weeks&#xD;
      during the high Pi phase (total Pi intake 1,200 mg/d) vs 2 capsules of Sodium Chloride (NaCl,&#xD;
      containing a total of 372mg of sodium) to match Na content to Sodium Phosphate without extra&#xD;
      Pi daily for 4 weeks during the low Pi phase (total Pi intake = 700 mg/d).&#xD;
&#xD;
      The total Na intake during the entire study will be at recommended level of 2,300 mg/d.&#xD;
      Investigational drug service at UT Southwestern will dispense Sodium Phosphate vs. NaCl&#xD;
      tablets tablets and the study subjects will be blinded to the type of supplement they&#xD;
      receive.&#xD;
&#xD;
      During the periods of high and low Pi phases, we will monitor 24-hr UPiV to ensure adherence.&#xD;
      Since approximately 70% of ingested Pi is absorbed and excreted in the urine, we expect 24-hr&#xD;
      UPiV excretion to be approximately 840 mg during the high Pi phase and 490 mg during the low&#xD;
      Pi phase. If 24-hr UPiV is &lt; 800 mg during the high Pi diet or &gt; 500 mg during the low Pi&#xD;
      diet, the research dietitian will provide additional counseling to improve adherence to the&#xD;
      menu plan. If needed, the research diet will be altered to be more compatible with subject&#xD;
      preference. 24-hr UPiV will be reassessed within 1 week in these individuals. If the levels&#xD;
      remain below goal, subjects will be excluded from the study.&#xD;
&#xD;
      24-hr urinary Pi, Na, K, Cr, and Ca excretion will be assessed after weeks 2 and 4 of the low&#xD;
      and high Pi phases. Serum electrolytes and Pi will be monitored every 2 weeks. Serum FGF23,&#xD;
      PTH, and soluble Klotho levels and 24-h ambulatory BP will be obtained after 4 weeks on the&#xD;
      study diet. Then, on a separate day, we will assess muscle SNA and BP at rest and during&#xD;
      rhythmic handgrip of 30% and 45% each for 3 minutes. Additionally, we will test the role of&#xD;
      dietary Pi on the response to isometric exercise by assessing SNA and BP during static&#xD;
      handgrip at 30% MVC for 2 minutes followed by post exercise circulatory arrest (PECA). The&#xD;
      latter maneuver will maximally activate the metaboreflex. Each exercise intervention will be&#xD;
      separated by at least 30 minutes. The order of exercise intervention will be randomized.&#xD;
      Subsequently, subjects will stop the first study supplement and undergo washout for 2 weeks.&#xD;
      After 2 weeks of washout, they will receive the 2nd study supplement. Measurement of 24-h&#xD;
      ambulatory BP, SNA at rest and during handgrip exercise will be repeated in the same fashion.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 16, 2017</start_date>
  <completion_date type="Actual">September 30, 2022</completion_date>
  <primary_completion_date type="Actual">September 30, 2022</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>24-hour Blood Pressure measured by Ambulatory Blood Pressure Monitor.</measure>
    <time_frame>4 weeks</time_frame>
    <description>Blood pressure will be measured through an ambulatory blood pressure monitoring device by Space Labs # 90217, worn by each participant after completing each phase, This will suggest if participant's blood pressure increased during high phosphorus phase as compared to low phosphorus phase.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Muscle Sympathetic Nerve Activity (MSNA)</measure>
    <time_frame>4 weeks after high phosphorus and 4 weeks after low phosphorus diet</time_frame>
    <description>MSNA will be measured during both diet phases using microelectrodes inserted in the peroneal nerve. This will assess the impact of phosphate intake on MSNA.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">94</enrollment>
  <condition>Hypertension</condition>
  <arm_group>
    <arm_group_label>High Phosphate Phase</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All subjects will be on a low Pi diet containing 700mg/day of phosphate and 2 capsules of sodium phosphate with 500mg/day of phosphate for 4 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Low Phosphate Phase</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>All subjects will be on a low Pi diet containing 700mg/day of phosphate and 2 capsules of sodium chloride for 4 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>High Phosphate Phase</intervention_name>
    <description>2 capsules of sodium phosphate with 500mg/day of phosphate.</description>
    <arm_group_label>High Phosphate Phase</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Low Phosphate Phase</intervention_name>
    <description>2 capsules of sodium chloride.</description>
    <arm_group_label>Low Phosphate Phase</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria: (answer must be yes to all to enter trial; check yes or no)&#xD;
&#xD;
        º ≥ 18 years of age&#xD;
&#xD;
        º Stage 1 Prehypertension (office BP 120-129/80-84 mmHg and normal ABPM &lt;130/80)&#xD;
&#xD;
        Exclusion Criteria: (answer must be no to all to enter trial)&#xD;
&#xD;
        º Diabetes mellitus or other systemic disease&#xD;
&#xD;
        º Cardiopulmonary disease&#xD;
&#xD;
        º Treatment with antihypertensive medications&#xD;
&#xD;
        º eGFR&lt; 60 ml/min/1.73m2&#xD;
&#xD;
        º Pregnancy&#xD;
&#xD;
        º Hypersensitivity to nitroprusside or phenylephrine&#xD;
&#xD;
        º Psychiatric illness&#xD;
&#xD;
        º H/o substance abuse or current smoker&#xD;
&#xD;
        º H/o malignancy&#xD;
&#xD;
        º Serum Phos &lt;2.4 mg/dL or &gt;4.5 mg/dL&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Wapen Vongpatanasin, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>UT southwestern</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Texas Southwestern Medical Center at Dallas</name>
      <address>
        <city>Dallas</city>
        <state>Texas</state>
        <zip>75390</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <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>
  <reference>
    <citation>Sullivan CM, Leon JB, Sehgal AR. Phosphorus-containing food additives and the accuracy of nutrient databases: implications for renal patients. J Ren Nutr. 2007 Sep;17(5):350-4. doi: 10.1053/j.jrn.2007.05.008.</citation>
    <PMID>17720105</PMID>
  </reference>
  <reference>
    <citation>Benini O, D'Alessandro C, Gianfaldoni D, Cupisti A. Extra-phosphate load from food additives in commonly eaten foods: a real and insidious danger for renal patients. J Ren Nutr. 2011 Jul;21(4):303-8. doi: 10.1053/j.jrn.2010.06.021. Epub 2010 Nov 5.</citation>
    <PMID>21055967</PMID>
  </reference>
  <reference>
    <citation>Ketteler M, Wolf M, Hahn K, Ritz E. Phosphate: a novel cardiovascular risk factor. Eur Heart J. 2013 Apr;34(15):1099-101. doi: 10.1093/eurheartj/ehs247. Epub 2012 Oct 7. No abstract available.</citation>
    <PMID>23045267</PMID>
  </reference>
  <reference>
    <citation>Karp H, Ekholm P, Kemi V, Itkonen S, Hirvonen T, Narkki S, Lamberg-Allardt C. Differences among total and in vitro digestible phosphorus content of plant foods and beverages. J Ren Nutr. 2012 Jul;22(4):416-22. doi: 10.1053/j.jrn.2011.04.004. Epub 2011 Jul 13.</citation>
    <PMID>21741857</PMID>
  </reference>
  <reference>
    <citation>Suzuki Y, Mitsushima S, Kato A, Yamaguchi T, Ichihara S. High-phosphorus/zinc-free diet aggravates hypertension and cardiac dysfunction in a rat model of the metabolic syndrome. Cardiovasc Pathol. 2014 Jan-Feb;23(1):43-9. doi: 10.1016/j.carpath.2013.06.004. Epub 2013 Aug 8.</citation>
    <PMID>23932324</PMID>
  </reference>
  <reference>
    <citation>Scanni R, vonRotz M, Jehle S, Hulter HN, Krapf R. The human response to acute enteral and parenteral phosphate loads. J Am Soc Nephrol. 2014 Dec;25(12):2730-9. doi: 10.1681/ASN.2013101076. Epub 2014 May 22.</citation>
    <PMID>24854273</PMID>
  </reference>
  <reference>
    <citation>Hu MC, Shi M, Cho HJ, Adams-Huet B, Paek J, Hill K, Shelton J, Amaral AP, Faul C, Taniguchi M, Wolf M, Brand M, Takahashi M, Kuro-O M, Hill JA, Moe OW. Klotho and phosphate are modulators of pathologic uremic cardiac remodeling. J Am Soc Nephrol. 2015 Jun;26(6):1290-302. doi: 10.1681/ASN.2014050465. Epub 2014 Oct 17.</citation>
    <PMID>25326585</PMID>
  </reference>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>July 26, 2017</study_first_submitted>
  <study_first_submitted_qc>July 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 31, 2017</study_first_posted>
  <last_update_submitted>November 2, 2022</last_update_submitted>
  <last_update_submitted_qc>November 2, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 4, 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>Wanpen Vongpatanasin</investigator_full_name>
    <investigator_title>Professor of Medicine</investigator_title>
  </responsible_party>
  <keyword>Hypertension</keyword>
  <keyword>High phosphorus diet</keyword>
  <keyword>FGF 23</keyword>
  <keyword>24 hour ambulatory blood pressure</keyword>
  <keyword>Muscle sympathetic nerve</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>Undecided</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03234361
org study id: STU 012017-052
nct id: NCT03234361
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
An increasing number of studies have indicated that most fast food and common grocery items,
      contain large amount of inorganic phosphate-based food additives , which are highly
      absorbable. The long-term cardiovascular consequences of a high phosphate diet are unknown
      but the existing database implicates phosphate excess as an independent risk factor for
      cardiovascular events in individuals with and without chronic kidney diseases (CKD). High
      phosphate consumption clearly induces BP elevation in rats with normal kidneys. However, the
      mechanisms underlying phosphate-induced hypertension and the relevance of these rodent
      studies to human hypertension have not been determined. We seek to investigate the role of
      high phosphate diet in human hypertension and assess the effect of high phosphate diet on
      muscle sympathetic nerve activity and the exercise pressor reflex.
Animal studies suggest that high phosphate diet raises blood pressure but the mechanism
      underlying this phenomenon is not known. To study the effect of high phosphorus diet on blood
      pressure in humans, we will perform randomized crossover studies in stage 1 prehypertensive
      subjects. To ensure stable Pi intake prior to randomization, Pi consumption will be estimated
      by food recall during a run-in and washout phase for 2 consecutive days, using the Automated
      Self-Administered 24-Hour (ASA24®) Dietary Assessment Tool
      (https://epi.grants.cancer.gov/asa24/). After the run-in period, all subjects will be
      maintained on a low Pi diet (700 mg/d) and a low Na diet of approximately 1,930 mg/d
      throughout the study for 8 weeks. Subjects will also be randomized to receive Sodium
      Phosphate 2 capsules daily (containing a total of 500 mg of Pi, 372mg of sodium) for 4 weeks
      during the high Pi phase (total Pi intake 1,200 mg/d) vs 2 capsules of Sodium Chloride (NaCl,
      containing a total of 372mg of sodium) to match Na content to Sodium Phosphate without extra
      Pi daily for 4 weeks during the low Pi phase (total Pi intake = 700 mg/d).

      The total Na intake during the entire study will be at recommended level of 2,300 mg/d.
      Investigational drug service at UT Southwestern will dispense Sodium Phosphate vs. NaCl
      tablets tablets and the study subjects will be blinded to the type of supplement they
      receive.

      During the periods of high and low Pi phases, we will monitor 24-hr UPiV to ensure adherence.
      Since approximately 70% of ingested Pi is absorbed and excreted in the urine, we expect 24-hr
      UPiV excretion to be approximately 840 mg during the high Pi phase and 490 mg during the low
      Pi phase. If 24-hr UPiV is < 800 mg during the high Pi diet or > 500 mg during the low Pi
      diet, the research dietitian will provide additional counseling to improve adherence to the
      menu plan. If needed, the research diet will be altered to be more compatible with subject
      preference. 24-hr UPiV will be reassessed within 1 week in these individuals. If the levels
      remain below goal, subjects will be excluded from the study.

      24-hr urinary Pi, Na, K, Cr, and Ca excretion will be assessed after weeks 2 and 4 of the low
      and high Pi phases. Serum electrolytes and Pi will be monitored every 2 weeks. Serum FGF23,
      PTH, and soluble Klotho levels and 24-h ambulatory BP will be obtained after 4 weeks on the
      study diet. Then, on a separate day, we will assess muscle SNA and BP at rest and during
      rhythmic handgrip of 30% and 45% each for 3 minutes. Additionally, we will test the role of
      dietary Pi on the response to isometric exercise by assessing SNA and BP during static
      handgrip at 30% MVC for 2 minutes followed by post exercise circulatory arrest (PECA). The
      latter maneuver will maximally activate the metaboreflex. Each exercise intervention will be
      separated by at least 30 minutes. The order of exercise intervention will be randomized.
      Subsequently, subjects will stop the first study supplement and undergo washout for 2 weeks.
      After 2 weeks of washout, they will receive the 2nd study supplement. Measurement of 24-h
      ambulatory BP, SNA at rest and during handgrip exercise will be repeated in the same fashion.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: 24-hour Blood Pressure measured by Ambulatory Blood Pressure Monitor.
time frame: 4 weeks
description: Blood pressure will be measured through an ambulatory blood pressure monitoring device by Space Labs # 90217, worn by each participant after completing each phase, This will suggest if participant's blood pressure increased during high phosphorus phase as compared to low phosphorus phase.
measure: Muscle Sympathetic Nerve Activity (MSNA)
time frame: 4 weeks after high phosphorus and 4 weeks after low phosphorus diet
description: MSNA will be measured during both diet phases using microelectrodes inserted in the peroneal nerve. This will assess the impact of phosphate intake on MSNA.
arm group label: High Phosphate Phase
arm group type: Experimental
description: All subjects will be on a low Pi diet containing 700mg/day of phosphate and 2 capsules of sodium phosphate with 500mg/day of phosphate for 4 weeks.
arm group label: Low Phosphate Phase
arm group type: Placebo Comparator
description: All subjects will be on a low Pi diet containing 700mg/day of phosphate and 2 capsules of sodium chloride for 4 weeks.
intervention type: Dietary Supplement
intervention name: High Phosphate Phase
description: 2 capsules of sodium phosphate with 500mg/day of phosphate.
arm group label: High Phosphate Phase
intervention type: Dietary Supplement
intervention name: Low Phosphate Phase
description: 2 capsules of sodium chloride.
arm group label: Low Phosphate Phase
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Wapen Vongpatanasin, MD
role: Principal Investigator
affiliation: UT southwestern
facility: 
facility: 
country: United States
citation: Sullivan CM, Leon JB, Sehgal AR. Phosphorus-containing food additives and the accuracy of nutrient databases: implications for renal patients. J Ren Nutr. 2007 Sep;17(5):350-4. doi: 10.1053/j.jrn.2007.05.008.
PMID: 17720105
citation: Benini O, D'Alessandro C, Gianfaldoni D, Cupisti A. Extra-phosphate load from food additives in commonly eaten foods: a real and insidious danger for renal patients. J Ren Nutr. 2011 Jul;21(4):303-8. doi: 10.1053/j.jrn.2010.06.021. Epub 2010 Nov 5.
PMID: 21055967
citation: Ketteler M, Wolf M, Hahn K, Ritz E. Phosphate: a novel cardiovascular risk factor. Eur Heart J. 2013 Apr;34(15):1099-101. doi: 10.1093/eurheartj/ehs247. Epub 2012 Oct 7. No abstract available.
PMID: 23045267
citation: Karp H, Ekholm P, Kemi V, Itkonen S, Hirvonen T, Narkki S, Lamberg-Allardt C. Differences among total and in vitro digestible phosphorus content of plant foods and beverages. J Ren Nutr. 2012 Jul;22(4):416-22. doi: 10.1053/j.jrn.2011.04.004. Epub 2011 Jul 13.
PMID: 21741857
citation: Suzuki Y, Mitsushima S, Kato A, Yamaguchi T, Ichihara S. High-phosphorus/zinc-free diet aggravates hypertension and cardiac dysfunction in a rat model of the metabolic syndrome. Cardiovasc Pathol. 2014 Jan-Feb;23(1):43-9. doi: 10.1016/j.carpath.2013.06.004. Epub 2013 Aug 8.
PMID: 23932324
citation: Scanni R, vonRotz M, Jehle S, Hulter HN, Krapf R. The human response to acute enteral and parenteral phosphate loads. J Am Soc Nephrol. 2014 Dec;25(12):2730-9. doi: 10.1681/ASN.2013101076. Epub 2014 May 22.
PMID: 24854273
citation: Hu MC, Shi M, Cho HJ, Adams-Huet B, Paek J, Hill K, Shelton J, Amaral AP, Faul C, Taniguchi M, Wolf M, Brand M, Takahashi M, Kuro-O M, Hill JA, Moe OW. Klotho and phosphate are modulators of pathologic uremic cardiac remodeling. J Am Soc Nephrol. 2015 Jun;26(6):1290-302. doi: 10.1681/ASN.2014050465. Epub 2014 Oct 17.
PMID: 25326585
responsible party type: Principal Investigator
investigator affiliation: University of Texas Southwestern Medical Center
investigator full name: Wanpen Vongpatanasin
investigator title: Professor of Medicine
mesh term: Hypertension
sharing ipd: Undecided