<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/NCT01665534</url>
  </required_header>
  <id_info>
    <org_study_id>SS-011-RC</org_study_id>
    <nct_id>NCT01665534</nct_id>
  </id_info>
  <brief_title>Inflammatory Response to Salt in Essential Hypertension</brief_title>
  <official_title>Procalcitonin and the Inflammatory Response to Salt in Essential Hypertension: a Randomised Cross-over Clinical Trial.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Carmine Zoccali</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Fondazione C.N.R./Regione Toscana &quot;G. Monasterio&quot;, Pisa, Italy</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Salt is a main environmental risk factor involved in atherosclerotic complications and in the&#xD;
      high risk of a variety of cardiovascular (CV) diseases including hypertension, left&#xD;
      ventricular hypertrophy (LVH), chronic kidney disease (CKD) and heart failure. The link&#xD;
      between sodium and cardiovascular disease is complex and involves blood pressure (BP)&#xD;
      dependent and independent mechanisms. Among the latter, inflammation is suspected to be a&#xD;
      major effector of arterial damage brought about by the salt excess in animal models. In&#xD;
      humans, C-Reactive Protein (CRP) associated directly with dietary salt intake in a&#xD;
      population-based survey but such a link was not confirmed in other studies. This apparent&#xD;
      discrepancy may depend on the observational (i.e., open to confounding) nature of these&#xD;
      studies. Inflammatory cytokines are essential for the short term systemic response to&#xD;
      environmental stressors. For example it is well established that TNF-α, a cytokine that&#xD;
      modulates renin gene expression by signalling via TNF-receptor 2, exerts a protective effect&#xD;
      for the myocardium in a stressful condition like experimental cardiac ischemia while low&#xD;
      levels of adiponectin have a detrimental effect in the same setting. Thus, the&#xD;
      inflammation-sodium relationship may be non-linear and severe salt restriction may actually&#xD;
      trigger inflammation, a hypothesis suggested by the observation that biomarkers of&#xD;
      inflammation rose in response to salt depletion in a sequential study in essential&#xD;
      hypertensives. However, the lack of randomization in this study leaves open the question&#xD;
      whether the observed pro-inflammatory effect was due to change in salt intake or to other,&#xD;
      unmeasured time-dependent effect(s). With this background in mind the investigators setup a&#xD;
      randomized, single masked, cross-over study to assess the effect of a short term very low&#xD;
      salt diet on biomarkers of innate immunity in patients with uncomplicated essential&#xD;
      hypertension.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The protocol was in conformity with the ethical guidelines of our institution and informed&#xD;
      consent was obtained by each participant. During the run-in phase of the study, which lasted&#xD;
      1 month, patients underwent standard arterial pressure measurements on two separate occasions&#xD;
      (at least 10 days apart) and were considered eligible for the study if their casual arterial&#xD;
      pressure exceeded 140/90 mmHg.&#xD;
&#xD;
      Patients were randomized to either a 10-20 mmol sodium diet plus sodium tablets (180 mEq/die)&#xD;
      to achieve a 200 mmol intake /day, or the same diet plus identical placebo tablets, each for&#xD;
      two weeks. At the end of each of these two-week periods, all patients underwent a 24-hours&#xD;
      urine collection, a fasting blood sampling and a 24h ambulatory blood pressure monitoring&#xD;
      (see below).&#xD;
&#xD;
      Ambulatory monitoring was performed with a device conforming with the AAMI criteria (Takeda&#xD;
      2420 model 7, Takeda Medical, Osaka, Japan). Between 08.30 and 11.30 hours, after placement&#xD;
      of the device in the left (non-dominant) arm, the patients rested quietly in an armchair for&#xD;
      15 min and arterial pressure was taken automatically three times (at 5 min intervals).&#xD;
      Patients then went home and remained indoors throughout all the recording day. They were&#xD;
      instructed to spend a relaxed, quiet day avoiding physical efforts. Recordings were set at 15&#xD;
      min intervals between the 07.00 to 22.00 hours and every 30 min during the sleeping hours&#xD;
      (22.00 pm to 07.00). The calibration of the ambulatory recorder was performed against a&#xD;
      mercury sphygmomanometer before each recording. Patients were classified as salt-sensitive if&#xD;
      the changes in mean arterial pressure between low and high salt diet was &gt; 10%.&#xD;
&#xD;
      Blood sampling was performed on the last day of each period after 45 minutes supine rest. The&#xD;
      patients were specifically instructed not to alter their smoking habits, alcohol and coffee&#xD;
      intake and not to modify the level of physical activity throughout the study.&#xD;
&#xD;
      Urinary sodium was measured by an ion-selective electrode using a Beckman (Fullertone, CA,&#xD;
      USA) EA-2 Electrolyte Analyser. Serum and urine creatinine was measured by a colorimetric&#xD;
      method using a COBAS-Mira spectrophotometer (Roche, Basel, Switzerland). The measurements of&#xD;
      plasma renin activity (PRA) and plasma aldosterone concentration were performed by&#xD;
      radioimmunoassay (RIA) using a commercially available kit (Technogenetics-Milan, Italy).&#xD;
&#xD;
      Biomarkers of inflammation and endothelial integrity/function High sensitivity C-Reactive&#xD;
      Protein (hs-CRP) was measured in plasma by a nephelometric method (Dade-Behring, Scoppito,&#xD;
      L'Aquila, Italy) (intra-assay CV: 3.5%; inter-assay CV: 3.4%; normal range &lt; 2.87 mg/L).&#xD;
      Interleukin-6 (intra-assay CV: 2.6%; inter-assay CV: 4.5%, normal range &lt; 12.5 pg/mL) and&#xD;
      TNF-α (intra-assay CV: 4.7%; inter-assay CV: 5.8%, normal range &lt; 15.6 pg/mL) were measured&#xD;
      by commercially available RIA kits (R&amp;D System, Minneapolis, USA). High sensitivity&#xD;
      procalcitonin (PCT) (intra-assay CV: 2-3% normal value &lt; 0.05 ng/mL) was measured by an&#xD;
      immunofluorescence method (Kriptor, BRAHMS, Henningsdorf, Germany). Plasma Adiponectin&#xD;
      (intra-assay CV: 3.9%; inter-assay CV: 8.4%) and Leptin (intra-assay CV: 5.0%; inter-assay&#xD;
      CV: 4.5%) were measured by a RIA kit (Linco Research Missouri, USA).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>March 2010</start_date>
  <completion_date type="Actual">March 2011</completion_date>
  <primary_completion_date type="Actual">March 2011</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change from baseline of inflammatory biomarkers (TNF-alpha, procalcitonin, IL-6, C-Reactive Protein, adiponectin and leptin) in response to salt intake.</measure>
    <time_frame>Inflammatory biomarkers were measured at baseline and at the end of two-week diet periods.</time_frame>
    <description>Patients were randomized to either a 10-20 mmol sodium diet plus sodium tablets (180 mEq/die) to achieve a 200 mmol intake /day, or the same diet plus identical placebo tablets, each for two weeks.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Blood pressure response to salt intake.</measure>
    <time_frame>24h ambulatory blood pressure was measured at baseline and at the end of two-week diet periods.</time_frame>
    <description>Patients were randomized to either a 10-20 mmol sodium diet plus sodium tablets (180 mEq/die) to achieve a 200 mmol intake /day, or the same diet plus identical placebo tablets, each for two weeks.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">32</enrollment>
  <condition>Essential Hypertension.</condition>
  <arm_group>
    <arm_group_label>Effect of salt intake</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>During the high salt intake period, patients received a 10-20 mmol sodium diet plus sodium tablets (180 mEq/die) to achieve a 200 mmol intake /day for two weeks. During the low salt intake period, patients received a 10-20 mmol sodium diet + placebo tablets for two weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>High salt intake</intervention_name>
    <description>During the high salt intake period, patients received a 10-20 mmol sodium diet plus sodium tablets (180 mEq/die) to achieve a 200 mmol intake /day for two weeks</description>
    <arm_group_label>Effect of salt intake</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Patients with uncomplicated, untreated essential hypertension (age&gt;18 years).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Patients with secondary hypertension, liver disease, neoplasia and other chronic disease.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Carmine Zoccali, Prof.</last_name>
    <role>Study Chair</role>
    <affiliation>Nephrology, Dialysis and Transplantation Unit and CNR-IBIM</affiliation>
  </overall_official>
  <verification_date>August 2012</verification_date>
  <study_first_submitted>August 7, 2012</study_first_submitted>
  <study_first_submitted_qc>August 12, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 15, 2012</study_first_posted>
  <last_update_submitted>August 12, 2012</last_update_submitted>
  <last_update_submitted_qc>August 12, 2012</last_update_submitted_qc>
  <last_update_posted type="Estimate">August 15, 2012</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Fondazione C.N.R./Regione Toscana &quot;G. Monasterio&quot;, Pisa, Italy</investigator_affiliation>
    <investigator_full_name>Carmine Zoccali</investigator_full_name>
    <investigator_title>Director of the Nephrology, Dialysis and Transplantation Unit and Project Leader of the Section of &quot;Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension&quot; of CNR-IBIM, Reggio Calabria, Italy</investigator_title>
  </responsible_party>
  <keyword>hypertension</keyword>
  <keyword>inflammation</keyword>
  <keyword>salt intake</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypertension</mesh_term>
    <mesh_term>Essential Hypertension</mesh_term>
  </condition_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/NCT01665534
org study id: SS-011-RC
nct id: NCT01665534
lead sponsor: 
has dmc: No
Salt is a main environmental risk factor involved in atherosclerotic complications and in the
      high risk of a variety of cardiovascular (CV) diseases including hypertension, left
      ventricular hypertrophy (LVH), chronic kidney disease (CKD) and heart failure. The link
      between sodium and cardiovascular disease is complex and involves blood pressure (BP)
      dependent and independent mechanisms. Among the latter, inflammation is suspected to be a
      major effector of arterial damage brought about by the salt excess in animal models. In
      humans, C-Reactive Protein (CRP) associated directly with dietary salt intake in a
      population-based survey but such a link was not confirmed in other studies. This apparent
      discrepancy may depend on the observational (i.e., open to confounding) nature of these
      studies. Inflammatory cytokines are essential for the short term systemic response to
      environmental stressors. For example it is well established that TNF-α, a cytokine that
      modulates renin gene expression by signalling via TNF-receptor 2, exerts a protective effect
      for the myocardium in a stressful condition like experimental cardiac ischemia while low
      levels of adiponectin have a detrimental effect in the same setting. Thus, the
      inflammation-sodium relationship may be non-linear and severe salt restriction may actually
      trigger inflammation, a hypothesis suggested by the observation that biomarkers of
      inflammation rose in response to salt depletion in a sequential study in essential
      hypertensives. However, the lack of randomization in this study leaves open the question
      whether the observed pro-inflammatory effect was due to change in salt intake or to other,
      unmeasured time-dependent effect(s). With this background in mind the investigators setup a
      randomized, single masked, cross-over study to assess the effect of a short term very low
      salt diet on biomarkers of innate immunity in patients with uncomplicated essential
      hypertension.
The protocol was in conformity with the ethical guidelines of our institution and informed
      consent was obtained by each participant. During the run-in phase of the study, which lasted
      1 month, patients underwent standard arterial pressure measurements on two separate occasions
      (at least 10 days apart) and were considered eligible for the study if their casual arterial
      pressure exceeded 140/90 mmHg.

      Patients were randomized to either a 10-20 mmol sodium diet plus sodium tablets (180 mEq/die)
      to achieve a 200 mmol intake /day, or the same diet plus identical placebo tablets, each for
      two weeks. At the end of each of these two-week periods, all patients underwent a 24-hours
      urine collection, a fasting blood sampling and a 24h ambulatory blood pressure monitoring
      (see below).

      Ambulatory monitoring was performed with a device conforming with the AAMI criteria (Takeda
      2420 model 7, Takeda Medical, Osaka, Japan). Between 08.30 and 11.30 hours, after placement
      of the device in the left (non-dominant) arm, the patients rested quietly in an armchair for
      15 min and arterial pressure was taken automatically three times (at 5 min intervals).
      Patients then went home and remained indoors throughout all the recording day. They were
      instructed to spend a relaxed, quiet day avoiding physical efforts. Recordings were set at 15
      min intervals between the 07.00 to 22.00 hours and every 30 min during the sleeping hours
      (22.00 pm to 07.00). The calibration of the ambulatory recorder was performed against a
      mercury sphygmomanometer before each recording. Patients were classified as salt-sensitive if
      the changes in mean arterial pressure between low and high salt diet was > 10%.

      Blood sampling was performed on the last day of each period after 45 minutes supine rest. The
      patients were specifically instructed not to alter their smoking habits, alcohol and coffee
      intake and not to modify the level of physical activity throughout the study.

      Urinary sodium was measured by an ion-selective electrode using a Beckman (Fullertone, CA,
      USA) EA-2 Electrolyte Analyser. Serum and urine creatinine was measured by a colorimetric
      method using a COBAS-Mira spectrophotometer (Roche, Basel, Switzerland). The measurements of
      plasma renin activity (PRA) and plasma aldosterone concentration were performed by
      radioimmunoassay (RIA) using a commercially available kit (Technogenetics-Milan, Italy).

      Biomarkers of inflammation and endothelial integrity/function High sensitivity C-Reactive
      Protein (hs-CRP) was measured in plasma by a nephelometric method (Dade-Behring, Scoppito,
      L'Aquila, Italy) (intra-assay CV: 3.5%; inter-assay CV: 3.4%; normal range < 2.87 mg/L).
      Interleukin-6 (intra-assay CV: 2.6%; inter-assay CV: 4.5%, normal range < 12.5 pg/mL) and
      TNF-α (intra-assay CV: 4.7%; inter-assay CV: 5.8%, normal range < 15.6 pg/mL) were measured
      by commercially available RIA kits (R&D System, Minneapolis, USA). High sensitivity
      procalcitonin (PCT) (intra-assay CV: 2-3% normal value < 0.05 ng/mL) was measured by an
      immunofluorescence method (Kriptor, BRAHMS, Henningsdorf, Germany). Plasma Adiponectin
      (intra-assay CV: 3.9%; inter-assay CV: 8.4%) and Leptin (intra-assay CV: 5.0%; inter-assay
      CV: 4.5%) were measured by a RIA kit (Linco Research Missouri, USA).
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: Single (Investigator)
measure: Change from baseline of inflammatory biomarkers (TNF-alpha, procalcitonin, IL-6, C-Reactive Protein, adiponectin and leptin) in response to salt intake.
time frame: Inflammatory biomarkers were measured at baseline and at the end of two-week diet periods.
description: Patients were randomized to either a 10-20 mmol sodium diet plus sodium tablets (180 mEq/die) to achieve a 200 mmol intake /day, or the same diet plus identical placebo tablets, each for two weeks.
measure: Blood pressure response to salt intake.
time frame: 24h ambulatory blood pressure was measured at baseline and at the end of two-week diet periods.
description: Patients were randomized to either a 10-20 mmol sodium diet plus sodium tablets (180 mEq/die) to achieve a 200 mmol intake /day, or the same diet plus identical placebo tablets, each for two weeks.
arm group label: Effect of salt intake
arm group type: Experimental
description: During the high salt intake period, patients received a 10-20 mmol sodium diet plus sodium tablets (180 mEq/die) to achieve a 200 mmol intake /day for two weeks. During the low salt intake period, patients received a 10-20 mmol sodium diet + placebo tablets for two weeks.
intervention type: Behavioral
intervention name: High salt intake
description: During the high salt intake period, patients received a 10-20 mmol sodium diet plus sodium tablets (180 mEq/die) to achieve a 200 mmol intake /day for two weeks
arm group label: Effect of salt intake
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Carmine Zoccali, Prof.
role: Study Chair
affiliation: Nephrology, Dialysis and Transplantation Unit and CNR-IBIM
responsible party type: Sponsor-Investigator
investigator affiliation: Fondazione C.N.R./Regione Toscana "G. Monasterio", Pisa, Italy
investigator full name: Carmine Zoccali
investigator title: Director of the Nephrology, Dialysis and Transplantation Unit and Project Leader of the Section of "Clinical Epidemiology and Pathophysiology of Renal Diseases and Hypertension" of CNR-IBIM, Reggio Calabria, Italy
mesh term: Hypertension
mesh term: Essential Hypertension