<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/NCT03276598</url>
  </required_header>
  <id_info>
    <org_study_id>GENRES</org_study_id>
    <nct_id>NCT03276598</nct_id>
  </id_info>
  <brief_title>A Study on Molecular Genetics of Drug Responsiveness in Essential Hypertension</brief_title>
  <acronym>GENRES</acronym>
  <official_title>A Randomised Double-blind Cross-over Single-centre Study on Molecular Genetics of Drug Responsiveness in Essential Hypertension</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Helsinki University Central Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Helsinki University Central Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Blood pressure variation and the risk of essential hypertension have an important genetic&#xD;
      component. In most cases susceptibility to essential hypertension is likely determined by the&#xD;
      action of more than one gene.&#xD;
&#xD;
      The identification of genes causing susceptibility to hypertension is important, since it&#xD;
      would give new tools for the diagnosis and enable better etiological classification and&#xD;
      specific treatment of the disease.&#xD;
&#xD;
      The innovation of this study is to use the response to antihypertensive therapy as an&#xD;
      intermediate phenotype.&#xD;
&#xD;
      In the study, each subject uses one of four antihypertensive drugs, each as a monotherapy in&#xD;
      a rotational fashion, for 28 days in a randomized order. The antihypertensive drugs to be&#xD;
      tested include a thiazide diuretic, a beta-adrenergic antagonist, an angiotensin-II receptor&#xD;
      antagonist and a calcium channel blocker. The drugs that are selected for the study are&#xD;
      &quot;typical&quot; representatives of their groups and long-acting, and the dosages are sufficient but&#xD;
      well tolerable.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Blood pressure variation and the risk of essential hypertension have an important genetic&#xD;
      component. In most cases susceptibility to essential hypertension is likely determined by the&#xD;
      action of more than one gene.&#xD;
&#xD;
      The identification of genes causing susceptibility to hypertension is important, since it&#xD;
      would give new tools for the diagnosis and enable better etiological classification and&#xD;
      specific treatment of the disease. Finland is an ideal place for a study like this because of&#xD;
      the genetic homogeneity of the population, the relatively high prevalence of the disease and&#xD;
      the established protocols for the treatment and follow-up of hypertension in public health&#xD;
      care.&#xD;
&#xD;
      The molecular genetic studies on hypertension performed so far (by 1999) have primarily been&#xD;
      association studies, which are based on case-control classification and may produce erroneous&#xD;
      results. Particularly, a reliable phenotyping of cases and controls has been difficult.&#xD;
      Consequently, more attention should be paid to the phenotyping of patients, and novel&#xD;
      intermediate phenotypes characteristic of certain subtypes of hypertension should be used to&#xD;
      facilitate the search for hypertension genes. The innovation of this study is to use the&#xD;
      response to antihypertensive therapy as an intermediate phenotype.&#xD;
&#xD;
      In the study, each subject uses one of four antihypertensive drugs, each as a monotherapy in&#xD;
      a rotational fashion, for 28 days in a randomized order. The antihypertensive drugs to be&#xD;
      tested include a thiazide diuretic, a beta-adrenergic antagonist, an angiotensin-II receptor&#xD;
      antagonist and a calcium channel blocker. The drugs that are selected for the study are&#xD;
      &quot;typical&quot; representatives of their groups and long-acting, and the dosages are sufficient but&#xD;
      well tolerable. The study design does not necessitate the use of equipotent doses of the&#xD;
      various agents, since the study is not designed to compare the antihypertensive effectiveness&#xD;
      of the study drugs or, due to the short treatment periods, their effects on clinical&#xD;
      endpoints.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 25, 1999</start_date>
  <completion_date type="Actual">April 1, 2004</completion_date>
  <primary_completion_date type="Actual">April 1, 2004</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>
    <intervention_model_description>The design of the study is a randomized placebo-controlled cross-over study. The study starts with a run-in placebo period lasting for four weeks. The four monotherapy treatment periods last for four weeks and they are separated by placebo periods lasting also for four weeks. Randomization occurs after the first placebo period in blocks of 24 (all possible drug sequences).</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>The placebo tablets and drugs are packed in similar gelatin capsules.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Blood pressure</measure>
    <time_frame>4 weeks</time_frame>
    <description>Change in blood pressure</description>
  </primary_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Actual">233</enrollment>
  <condition>Hypertension</condition>
  <condition>Pharmacogenetics</condition>
  <arm_group>
    <arm_group_label>Amlodipine</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>One of the four monotherapy treatment periods.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Bisoprolol</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>One of the four monotherapy treatment periods.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Hydrochlorothiazide</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>One of the four monotherapy treatment periods.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Losartan</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>One of the four monotherapy treatment periods.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo treatment period.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Amlodipine</intervention_name>
    <description>Treatment for four weeks. Dose: 5 mg o.d.</description>
    <arm_group_label>Amlodipine</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bisoprolol</intervention_name>
    <description>Treatment for four weeks. Dose: 5 mg o.d.</description>
    <arm_group_label>Bisoprolol</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Hydrochlorothiazide</intervention_name>
    <description>Treatment for four weeks. Dose: 25 mg o.d.</description>
    <arm_group_label>Hydrochlorothiazide</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Losartan</intervention_name>
    <description>Treatment for four weeks. Dose: 50 mg o.d.</description>
    <arm_group_label>Losartan</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Treatment for four weeks. Dose: 1 tablet per day.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  essential hypertension diagnosed on an earlier occasion or during the present study&#xD;
             (three diastolic blood pressure readings &gt;=95 mmHg on separate occasions are&#xD;
             required).&#xD;
&#xD;
        Exclusion Criteria (before and during the study):&#xD;
&#xD;
          -  usage of three or more antihypertensive drugs&#xD;
&#xD;
          -  secondary hypertension&#xD;
&#xD;
          -  left ventricular hypertrophy&#xD;
&#xD;
          -  drug-treated diabetes mellitus&#xD;
&#xD;
          -  coronary heart disease&#xD;
&#xD;
          -  stroke and other disorders of cerebral circulation&#xD;
&#xD;
          -  renal disease&#xD;
&#xD;
          -  obstructive pulmonary disease&#xD;
&#xD;
          -  a disease treated with corticosteroids&#xD;
&#xD;
          -  a disease with drug treatment potentially influencing blood pressure levels&#xD;
&#xD;
          -  significant obesity (BMI &gt;=32 kg/m2)&#xD;
&#xD;
          -  allergic reaction towards any of the study drugs&#xD;
&#xD;
          -  The patient is excluded from the study if his blood pressure level rises to 200/120&#xD;
             mmHg or above during the study.&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Based on self-representation of gender identity</gender_description>
    <minimum_age>35 Years</minimum_age>
    <maximum_age>59 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kimmo K Kontula, Professor</last_name>
    <role>Principal Investigator</role>
    <affiliation>Helsinki University Central Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Helsinki University Central Hospital</name>
      <address>
        <city>Helsinki</city>
        <country>Finland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Finland</country>
  </location_countries>
  <results_reference>
    <citation>Hiltunen TP, Suonsyrja T, Hannila-Handelberg T, Paavonen KJ, Miettinen HE, Strandberg T, Tikkanen I, Tilvis R, Pentikainen PJ, Virolainen J, Kontula K. Predictors of antihypertensive drug responses: initial data from a placebo-controlled, randomized, cross-over study with four antihypertensive drugs (The GENRES Study). Am J Hypertens. 2007 Mar;20(3):311-8. doi: 10.1016/j.amjhyper.2006.09.006. Erratum In: Am J Hypertens. 2018 Nov 13;31(12):1333.</citation>
    <PMID>17324745</PMID>
  </results_reference>
  <results_reference>
    <citation>Suonsyrja T, Hannila-Handelberg T, Paavonen KJ, Miettinen HE, Donner K, Strandberg T, Tikkanen I, Tilvis R, Pentikainen PJ, Kontula K, Hiltunen TP. Laboratory tests as predictors of the antihypertensive effects of amlodipine, bisoprolol, hydrochlorothiazide and losartan in men: results from the randomized, double-blind, crossover GENRES Study. J Hypertens. 2008 Jun;26(6):1250-6. doi: 10.1097/HJH.0b013e3282fcc37f.</citation>
    <PMID>18475165</PMID>
  </results_reference>
  <results_reference>
    <citation>Hiltunen TP, Donner KM, Sarin AP, Saarela J, Ripatti S, Chapman AB, Gums JG, Gong Y, Cooper-DeHoff RM, Frau F, Glorioso V, Zaninello R, Salvi E, Glorioso N, Boerwinkle E, Turner ST, Johnson JA, Kontula KK. Pharmacogenomics of hypertension: a genome-wide, placebo-controlled cross-over study, using four classes of antihypertensive drugs. J Am Heart Assoc. 2015 Jan 26;4(1):e001521. doi: 10.1161/JAHA.115.001778.</citation>
    <PMID>25622599</PMID>
  </results_reference>
  <verification_date>September 2017</verification_date>
  <study_first_submitted>September 6, 2017</study_first_submitted>
  <study_first_submitted_qc>September 6, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 8, 2017</study_first_posted>
  <last_update_submitted>September 8, 2017</last_update_submitted>
  <last_update_submitted_qc>September 8, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">September 11, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Helsinki University Central Hospital</investigator_affiliation>
    <investigator_full_name>Kimmo Kontula</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <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>Losartan</mesh_term>
    <mesh_term>Amlodipine</mesh_term>
    <mesh_term>Hydrochlorothiazide</mesh_term>
    <mesh_term>Bisoprolol</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT03276598
org study id: GENRES
nct id: NCT03276598
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
Blood pressure variation and the risk of essential hypertension have an important genetic
      component. In most cases susceptibility to essential hypertension is likely determined by the
      action of more than one gene.

      The identification of genes causing susceptibility to hypertension is important, since it
      would give new tools for the diagnosis and enable better etiological classification and
      specific treatment of the disease.

      The innovation of this study is to use the response to antihypertensive therapy as an
      intermediate phenotype.

      In the study, each subject uses one of four antihypertensive drugs, each as a monotherapy in
      a rotational fashion, for 28 days in a randomized order. The antihypertensive drugs to be
      tested include a thiazide diuretic, a beta-adrenergic antagonist, an angiotensin-II receptor
      antagonist and a calcium channel blocker. The drugs that are selected for the study are
      "typical" representatives of their groups and long-acting, and the dosages are sufficient but
      well tolerable.
Blood pressure variation and the risk of essential hypertension have an important genetic
      component. In most cases susceptibility to essential hypertension is likely determined by the
      action of more than one gene.

      The identification of genes causing susceptibility to hypertension is important, since it
      would give new tools for the diagnosis and enable better etiological classification and
      specific treatment of the disease. Finland is an ideal place for a study like this because of
      the genetic homogeneity of the population, the relatively high prevalence of the disease and
      the established protocols for the treatment and follow-up of hypertension in public health
      care.

      The molecular genetic studies on hypertension performed so far (by 1999) have primarily been
      association studies, which are based on case-control classification and may produce erroneous
      results. Particularly, a reliable phenotyping of cases and controls has been difficult.
      Consequently, more attention should be paid to the phenotyping of patients, and novel
      intermediate phenotypes characteristic of certain subtypes of hypertension should be used to
      facilitate the search for hypertension genes. The innovation of this study is to use the
      response to antihypertensive therapy as an intermediate phenotype.

      In the study, each subject uses one of four antihypertensive drugs, each as a monotherapy in
      a rotational fashion, for 28 days in a randomized order. The antihypertensive drugs to be
      tested include a thiazide diuretic, a beta-adrenergic antagonist, an angiotensin-II receptor
      antagonist and a calcium channel blocker. The drugs that are selected for the study are
      "typical" representatives of their groups and long-acting, and the dosages are sufficient but
      well tolerable. The study design does not necessitate the use of equipotent doses of the
      various agents, since the study is not designed to compare the antihypertensive effectiveness
      of the study drugs or, due to the short treatment periods, their effects on clinical
      endpoints.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: The design of the study is a randomized placebo-controlled cross-over study. The study starts with a run-in placebo period lasting for four weeks. The four monotherapy treatment periods last for four weeks and they are separated by placebo periods lasting also for four weeks. Randomization occurs after the first placebo period in blocks of 24 (all possible drug sequences).
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: The placebo tablets and drugs are packed in similar gelatin capsules.
measure: Blood pressure
time frame: 4 weeks
description: Change in blood pressure
arm group label: Amlodipine
arm group type: Active Comparator
description: One of the four monotherapy treatment periods.
arm group label: Bisoprolol
arm group type: Active Comparator
description: One of the four monotherapy treatment periods.
arm group label: Hydrochlorothiazide
arm group type: Active Comparator
description: One of the four monotherapy treatment periods.
arm group label: Losartan
arm group type: Active Comparator
description: One of the four monotherapy treatment periods.
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo treatment period.
intervention type: Drug
intervention name: Amlodipine
description: Treatment for four weeks. Dose: 5 mg o.d.
arm group label: Amlodipine
intervention type: Drug
intervention name: Bisoprolol
description: Treatment for four weeks. Dose: 5 mg o.d.
arm group label: Bisoprolol
intervention type: Drug
intervention name: Hydrochlorothiazide
description: Treatment for four weeks. Dose: 25 mg o.d.
arm group label: Hydrochlorothiazide
intervention type: Drug
intervention name: Losartan
description: Treatment for four weeks. Dose: 50 mg o.d.
arm group label: Losartan
intervention type: Drug
intervention name: Placebo
description: Treatment for four weeks. Dose: 1 tablet per day.
arm group label: Placebo
criteria: 
gender: Male
gender based: Yes
gender description: Based on self-representation of gender identity
minimum age: 35 Years
maximum age: 59 Years
healthy volunteers: No
last name: Kimmo K Kontula, Professor
role: Principal Investigator
affiliation: Helsinki University Central Hospital
facility: 
country: Finland
citation: Hiltunen TP, Suonsyrja T, Hannila-Handelberg T, Paavonen KJ, Miettinen HE, Strandberg T, Tikkanen I, Tilvis R, Pentikainen PJ, Virolainen J, Kontula K. Predictors of antihypertensive drug responses: initial data from a placebo-controlled, randomized, cross-over study with four antihypertensive drugs (The GENRES Study). Am J Hypertens. 2007 Mar;20(3):311-8. doi: 10.1016/j.amjhyper.2006.09.006. Erratum In: Am J Hypertens. 2018 Nov 13;31(12):1333.
PMID: 17324745
citation: Suonsyrja T, Hannila-Handelberg T, Paavonen KJ, Miettinen HE, Donner K, Strandberg T, Tikkanen I, Tilvis R, Pentikainen PJ, Kontula K, Hiltunen TP. Laboratory tests as predictors of the antihypertensive effects of amlodipine, bisoprolol, hydrochlorothiazide and losartan in men: results from the randomized, double-blind, crossover GENRES Study. J Hypertens. 2008 Jun;26(6):1250-6. doi: 10.1097/HJH.0b013e3282fcc37f.
PMID: 18475165
citation: Hiltunen TP, Donner KM, Sarin AP, Saarela J, Ripatti S, Chapman AB, Gums JG, Gong Y, Cooper-DeHoff RM, Frau F, Glorioso V, Zaninello R, Salvi E, Glorioso N, Boerwinkle E, Turner ST, Johnson JA, Kontula KK. Pharmacogenomics of hypertension: a genome-wide, placebo-controlled cross-over study, using four classes of antihypertensive drugs. J Am Heart Assoc. 2015 Jan 26;4(1):e001521. doi: 10.1161/JAHA.115.001778.
PMID: 25622599
responsible party type: Principal Investigator
investigator affiliation: Helsinki University Central Hospital
investigator full name: Kimmo Kontula
investigator title: Professor
mesh term: Hypertension
mesh term: Essential Hypertension
mesh term: Losartan
mesh term: Amlodipine
mesh term: Hydrochlorothiazide
mesh term: Bisoprolol
sharing ipd: No