<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/NCT02214498</url>
  </required_header>
  <id_info>
    <org_study_id>2014_THYME</org_study_id>
    <nct_id>NCT02214498</nct_id>
  </id_info>
  <brief_title>Treatment of HYpertension: Morning Versus Evening</brief_title>
  <acronym>THYME</acronym>
  <official_title>Treatment of HYpertension: Morning Versus Evening</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Erasmus Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>ZonMw: The Netherlands Organisation for Health Research and Development</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Erasmus Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Rationale:&#xD;
&#xD;
      The nocturnal blood pressure mean is an independent and stronger predictor of cardiovascular&#xD;
      disease (CVD) risk than either daytime office, awake or 24hour mean blood pressure. In&#xD;
      general, when nocturnal blood pressure does not decline CVD risk is higher, usually referred&#xD;
      to as &quot;dippers&quot; versus &quot;non-dippers&quot;. Evening administration of treatment might lower&#xD;
      nocturnal blood pressure more effectively than morning administration, which is most commonly&#xD;
      advised.&#xD;
&#xD;
      The main hypothesis of this study is that evening administration of antihypertensive&#xD;
      medication might resume the dipping pattern in non-dippers and as a consequence might reduce&#xD;
      CVD risk more than morning administration.&#xD;
&#xD;
      Primary objective (in short):&#xD;
&#xD;
      -to prove that evening administration of enalapril/hydrochlorothiazide in non-dippers can&#xD;
      resume a dipping blood pressure pattern in non-dippers&#xD;
&#xD;
      Study design: A double-blind placebo-controlled cross-over study Each person will use for one&#xD;
      period of six weeks enalapril/hydrochlorothiazide in the morning and placebo in the evening,&#xD;
      and one period of six weeks the other way around&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date>May 2015</start_date>
  <completion_date type="Anticipated">May 2017</completion_date>
  <primary_completion_date type="Anticipated">May 2017</primary_completion_date>
  <phase>Phase 4</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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Average nocturnal blood pressure, percentage dipping and nadir of nocturnal blood pressure</measure>
    <time_frame>24 hours</time_frame>
    <description>At the end of each treatment period of six weeks, a 24 hour ambulatory blood pressure measurement will be performed</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Percentage of nocturnal diastolic blood pressure measurements below 65 mm hg</measure>
    <time_frame>24 hours</time_frame>
    <description>One safety issue on evening administration of antihypertensive treatment is that blood pressure might get too low. We will assess this especially in the dippers.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Urine: Sodium, potassium, protein, melatonin, creatinin</measure>
    <time_frame>Two times within 24 hours at the end of six weeks of treatment according to one of the two regimes</time_frame>
    <description>Excretion of sodium, potassium, protein and melatonin depend on the circadian clock. Therefore, differences between morning and evening administration of antihypertensive medication are tested</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma: enalapril, cortisol, melatonin, aldosterone, ACE activity, gene expression of clock genes</measure>
    <time_frame>Moring of 24 hour blood pressure measurement after six weeks of treatment according to a certain regime</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">120</enrollment>
  <condition>Essential Hypertension</condition>
  <arm_group>
    <arm_group_label>Enalapril/hydrochlorothiazide</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>This arm will start with six weeks of administration of enalapril/hydrochlorothiazide in the evening and placebo in the morning, followed by six weeks of active treatment in the morning and placebo in the evening</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>This arm will start with six weeks of morning administration of enalapril/hydrochlorothiazide in the morning and placebo in the evening, followed by six weeks of placebo in the morning and active treatment in the evening</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Enalapril/hydrochlorothiazide</intervention_name>
    <description>The intervention implies that morning and evening administration of enalapril/hydrochlorothiazide will be compared</description>
    <arm_group_label>Enalapril/hydrochlorothiazide</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>To be determined</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <arm_group_label>Enalapril/hydrochlorothiazide</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Essential hypertension&#xD;
&#xD;
          -  Stable blood pressure on treatment with Angiotensin Converting Enzyme Inhibitor (ACEI)&#xD;
             or Angiotensin II Receptor Blocker (ARB) and hydrochlorothiazide&#xD;
&#xD;
          -  Age between 18 and 85 years&#xD;
&#xD;
          -  WHO performance status 0-1&#xD;
&#xD;
          -  Available for a time period of 15 weeks&#xD;
&#xD;
          -  Written informed consent&#xD;
&#xD;
          -  Dippers: Nocturnal blood pressure fall of 10-20% of daytime values.20&#xD;
&#xD;
          -  Non-dippers: -Nocturnal blood pressure fall of &lt;10% of daytime values&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  secondary cause of hypertension&#xD;
&#xD;
          -  use of ARB because of intolerability (e.g. dry cough) of ACEI&#xD;
&#xD;
          -  nocturnal blood pressure fall of &gt;20% or rise&#xD;
&#xD;
          -  renal insufficiency (GFR&lt;60 ml/min)&#xD;
&#xD;
          -  shift work&#xD;
&#xD;
          -  pregnancy or wish to get pregnant&#xD;
&#xD;
          -  use of other antihypertensive medication than ACEI, ARB, hydrochlorothiazide or a&#xD;
             calcium channel blocker&#xD;
&#xD;
          -  use of sleeping medication&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jorie Versmissen, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Erasmus Medical Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Teun Van Gelder, Prof</last_name>
    <role>Study Director</role>
    <affiliation>Erasmus Medical Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Eric Sijbrands, Prof</last_name>
    <role>Study Chair</role>
    <affiliation>Erasmus Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Jorie Versmissen, MD, PhD</last_name>
    <email>j.versmissen@erasmusmc.nl</email>
  </overall_contact>
  <location>
    <facility>
      <name>Erasmus MC</name>
      <address>
        <city>Rotterdam</city>
        <country>Netherlands</country>
      </address>
    </facility>
    <contact>
      <last_name>Jorie Versmissen, MD, PhD</last_name>
      <email>j.versmissen@erasmusmc.nl</email>
    </contact>
    <investigator>
      <last_name>Jorie Versmissen, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>August 2014</verification_date>
  <study_first_submitted>August 8, 2014</study_first_submitted>
  <study_first_submitted_qc>August 8, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 12, 2014</study_first_posted>
  <last_update_submitted>August 13, 2014</last_update_submitted>
  <last_update_submitted_qc>August 13, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">August 15, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Erasmus Medical Center</investigator_affiliation>
    <investigator_full_name>Jorie Versmissen</investigator_full_name>
    <investigator_title>MD, PhD</investigator_title>
  </responsible_party>
  <keyword>Dipper</keyword>
  <keyword>Non-dipper</keyword>
  <keyword>Chronopharmacology</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>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hydrochlorothiazide</mesh_term>
    <mesh_term>Enalapril</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/NCT02214498
org study id: 2014_THYME
nct id: NCT02214498
lead sponsor: 
collaborator: 
has dmc: No
Rationale:

      The nocturnal blood pressure mean is an independent and stronger predictor of cardiovascular
      disease (CVD) risk than either daytime office, awake or 24hour mean blood pressure. In
      general, when nocturnal blood pressure does not decline CVD risk is higher, usually referred
      to as "dippers" versus "non-dippers". Evening administration of treatment might lower
      nocturnal blood pressure more effectively than morning administration, which is most commonly
      advised.

      The main hypothesis of this study is that evening administration of antihypertensive
      medication might resume the dipping pattern in non-dippers and as a consequence might reduce
      CVD risk more than morning administration.

      Primary objective (in short):

      -to prove that evening administration of enalapril/hydrochlorothiazide in non-dippers can
      resume a dipping blood pressure pattern in non-dippers

      Study design: A double-blind placebo-controlled cross-over study Each person will use for one
      period of six weeks enalapril/hydrochlorothiazide in the morning and placebo in the evening,
      and one period of six weeks the other way around
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Average nocturnal blood pressure, percentage dipping and nadir of nocturnal blood pressure
time frame: 24 hours
description: At the end of each treatment period of six weeks, a 24 hour ambulatory blood pressure measurement will be performed
measure: Percentage of nocturnal diastolic blood pressure measurements below 65 mm hg
time frame: 24 hours
description: One safety issue on evening administration of antihypertensive treatment is that blood pressure might get too low. We will assess this especially in the dippers.
measure: Urine: Sodium, potassium, protein, melatonin, creatinin
time frame: Two times within 24 hours at the end of six weeks of treatment according to one of the two regimes
description: Excretion of sodium, potassium, protein and melatonin depend on the circadian clock. Therefore, differences between morning and evening administration of antihypertensive medication are tested
measure: Plasma: enalapril, cortisol, melatonin, aldosterone, ACE activity, gene expression of clock genes
time frame: Moring of 24 hour blood pressure measurement after six weeks of treatment according to a certain regime
arm group label: Enalapril/hydrochlorothiazide
arm group type: Active Comparator
description: This arm will start with six weeks of administration of enalapril/hydrochlorothiazide in the evening and placebo in the morning, followed by six weeks of active treatment in the morning and placebo in the evening
arm group label: Placebo
arm group type: Placebo Comparator
description: This arm will start with six weeks of morning administration of enalapril/hydrochlorothiazide in the morning and placebo in the evening, followed by six weeks of placebo in the morning and active treatment in the evening
intervention type: Drug
intervention name: Enalapril/hydrochlorothiazide
description: The intervention implies that morning and evening administration of enalapril/hydrochlorothiazide will be compared
arm group label: Enalapril/hydrochlorothiazide
arm group label: Placebo
other name: To be determined
intervention type: Drug
intervention name: Placebo
arm group label: Enalapril/hydrochlorothiazide
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 85 Years
healthy volunteers: No
last name: Jorie Versmissen, MD, PhD
role: Principal Investigator
affiliation: Erasmus Medical Center
last name: Teun Van Gelder, Prof
role: Study Director
affiliation: Erasmus Medical Center
last name: Eric Sijbrands, Prof
role: Study Chair
affiliation: Erasmus Medical Center
last name: Jorie Versmissen, MD, PhD
email: j.versmissen@erasmusmc.nl
facility: 
contact: 
investigator: 
country: Netherlands
responsible party type: Principal Investigator
investigator affiliation: Erasmus Medical Center
investigator full name: Jorie Versmissen
investigator title: MD, PhD
mesh term: Hypertension
mesh term: Essential Hypertension
mesh term: Hydrochlorothiazide
mesh term: Enalapril