<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/NCT02264002</url>
  </required_header>
  <id_info>
    <org_study_id>503.203</org_study_id>
    <nct_id>NCT02264002</nct_id>
  </id_info>
  <brief_title>Pharmacodynamic Effects, Safety and Tolerability of Cilobradine, Compared to Metoprolol Succinate and Placebo in Healthy Volunteers</brief_title>
  <official_title>Pharmacodynamic Effects, Safety and Tolerability of 0.25 mg, 0.5 mg, 1 mg and 2 mg Cilobradine, Compared to 190 mg Metoprolol Succinate and Placebo, Administered p.o. Once Daily Over 14 Days to Healthy Volunteers in a Randomised, Placebo-controlled, Partly Double Blind Study, With a 4 mg/14 mg and 10 mg/20 mg Cilobradine Single Dose Versus Placebo Substudy (Double Blind, Three-fold Cross-over)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Boehringer Ingelheim</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Boehringer Ingelheim</source>
  <brief_summary>
    <textblock>
      Pharmacodynamic effects on heart rate (HR) at rest and during exercise and on flicker fusion&#xD;
      frequency (FFF), FFF method evaluation&#xD;
&#xD;
      Safety, tolerability and pharmacokinetics of cilobradine&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>February 2003</start_date>
  <primary_completion_date type="Actual">November 2003</primary_completion_date>
  <phase>Phase 1</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Changes in heart rate at rest</measure>
    <time_frame>Pre-dose, up to day 20 after first drug administration</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes in heart rate during exercise</measure>
    <time_frame>Pre-dose, up to day 20 after first drug administration</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes in flicker fusion frequency test (FFF)</measure>
    <time_frame>Pre-dose, up to day 20 after first drug administration</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of patients with clinically relevant changes in laboratory tests</measure>
    <time_frame>Pre-dose, up to 12 days after last drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients with clinically relevant changes in vital signs (blood pressure, heart rate)</measure>
    <time_frame>Pre-dose, up to 12 days after last drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients with clinically relevant changes in 12-lead ECG</measure>
    <time_frame>Pre-dose, up to 12 days after last drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients with adverse events</measure>
    <time_frame>Up to 12 days after last drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of global tolerability by the investigator</measure>
    <time_frame>Up to 12 days after last drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in peripheral FFF</measure>
    <time_frame>Pre-dose, up to day 20 after first drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the concentration-time curve of the analytes in plasma (AUC)</measure>
    <time_frame>Up to day 20 after start of first drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum measured concentration of the analytes in plasma (Cmax)</measure>
    <time_frame>Up to day 20 after start of first drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time from dosing to the maximum concentration of the analytes in plasma (tmax)</measure>
    <time_frame>Up to day 20 after start of first drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Terminal half-life of the analytes in plasma (t½)</measure>
    <time_frame>Up to day 20 after start of first drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean residence time of the analytes in the body after oral administration (MRTpo)</measure>
    <time_frame>Up to day 20 after start of first drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total clearance of the analytes in plasma following extravascular administration (CL/F)</measure>
    <time_frame>Up to day 20 after start of first drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apparent volume of distribution of the analytes during the terminal phase λz following extravascular administration (Vz/F)</measure>
    <time_frame>Up to day 20 after start of first drug administration</time_frame>
  </secondary_outcome>
  <number_of_arms>7</number_of_arms>
  <enrollment type="Actual">119</enrollment>
  <condition>Healthy</condition>
  <arm_group>
    <arm_group_label>Cilobradine low dose 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Cilobradine low dose 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Cilobradine medium dose</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Cilobradine high dose 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Cilobradine high dose 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Metoprolol succinate</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>1 tablet on day 1, day 2 followed by two tablets from day 3 to day 14</description>
  </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>Cilobradine low dose 1</intervention_name>
    <arm_group_label>Cilobradine low dose 1</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cilobradine low dose 2</intervention_name>
    <arm_group_label>Cilobradine low dose 2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cilobradine medium dose</intervention_name>
    <arm_group_label>Cilobradine medium dose</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cilobradine high dose 1</intervention_name>
    <arm_group_label>Cilobradine high dose 1</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cilobradine high dose 2</intervention_name>
    <arm_group_label>Cilobradine high dose 2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Metoprolol succinate tablets</intervention_name>
    <arm_group_label>Metoprolol succinate</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  All participants in the study should be healthy males and females. Volunteers will&#xD;
&#xD;
               -  be 21 to 55 years of age&#xD;
&#xD;
               -  have a Body Mass Index (BMI) of 19.9 to 29.9 kg/m2 and&#xD;
&#xD;
               -  have a resting heart rate (HR) (after 10 min. in the supine position) of more&#xD;
                  than 55 beats per minute (bpm)&#xD;
&#xD;
          -  Only post-menopausal females, or those who had had a hysterectomy, could participate.&#xD;
             All females had to have a negative pregnancy test&#xD;
&#xD;
          -  In accordance with good clinical practice (GCP) and the local legislation all&#xD;
             volunteers had to give their written informed consent prior to admission to the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any finding of the medical examination (including BP, HR and ECG) deviating from&#xD;
             normal and of clinical relevance&#xD;
&#xD;
          -  Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic,&#xD;
             immunological or hormonal disorders&#xD;
&#xD;
          -  Diseases of the central nervous system or psychiatric disorders or neurological&#xD;
             disorders&#xD;
&#xD;
          -  History of relevant orthostatic hypotension, fainting spells or blackouts&#xD;
&#xD;
          -  Chronic or relevant acute infections&#xD;
&#xD;
          -  History of allergy/hypersensitivity (including drug allergy) which is deemed relevant&#xD;
             to the trial as judged by the Investigator&#xD;
&#xD;
          -  Intake of drugs with a long half-life (&gt; 24 hours) within ten half-lives of the&#xD;
             respective drug before enrolment in the study&#xD;
&#xD;
          -  Use of any drugs which might influence the results of the trial within two weeks prior&#xD;
             to administration or during the trial&#xD;
&#xD;
          -  Participation in another trial with an investigational drug (≤ two months prior to&#xD;
             administration or during the trial)&#xD;
&#xD;
          -  Smoker (&gt; 10 cigarettes or &gt; 3 cigars of &gt; 3 pipes/day)&#xD;
&#xD;
          -  Inability to refrain from smoking on trial days&#xD;
&#xD;
          -  Alcohol abuse (&gt; 60 g/day)&#xD;
&#xD;
          -  Drug abuse&#xD;
&#xD;
          -  Blood donation (≥ 100 ml within four weeks prior to administration or during the&#xD;
             trial)&#xD;
&#xD;
          -  Excessive physical activities (within the last week before the study)&#xD;
&#xD;
          -  Any laboratory value outside the reference range of clinical relevance&#xD;
&#xD;
        Not necessarily clinically relevant abnormalities, but specific Exclusion criteria for the&#xD;
        drugs under study or for the study:&#xD;
&#xD;
          -  Consumption of more than 2 cups of coffee or black tea, or cola drinks, per day during&#xD;
             the last 6 weeks. However, subjects may participate if abstinence from the before&#xD;
             mentioned beverages is well tolerated during an interval of at least 2 weeks between&#xD;
             screening and first treatment&#xD;
&#xD;
          -  ECG: PQ interval &gt; 210 ms&#xD;
&#xD;
          -  HR at rest &lt; 55 bpm&#xD;
&#xD;
          -  Systolic BP &lt; 115 mmHg&#xD;
&#xD;
          -  Colour vision test abnormal. However, subjects may participate if they are able to&#xD;
             perform the flicker fusion test without difficulty&#xD;
&#xD;
          -  Psoriasis (own medical history or relative)&#xD;
&#xD;
          -  Relevant ophthalmological disease&#xD;
&#xD;
          -  History of asthma or obstructive pulmonary disease&#xD;
&#xD;
          -  History (including childhood) of traumatic injury to the head or brain&#xD;
&#xD;
          -  History (including childhood) of reduced seizure threshold&#xD;
&#xD;
          -  The following subjects will not be allowed to participate in the study&#xD;
&#xD;
               -  Any subject involved in professional transportation of human subjects&#xD;
&#xD;
               -  Any subject involved in operating dangerous machinery&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <link>
    <url>http://trials.boehringer-ingelheim.com</url>
    <description>Related Info</description>
  </link>
  <verification_date>October 2014</verification_date>
  <study_first_submitted>October 13, 2014</study_first_submitted>
  <study_first_submitted_qc>October 13, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 15, 2014</study_first_posted>
  <last_update_submitted>October 13, 2014</last_update_submitted>
  <last_update_submitted_qc>October 13, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 15, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Metoprolol</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/NCT02264002
org study id: 503.203
nct id: NCT02264002
lead sponsor: 
Pharmacodynamic effects on heart rate (HR) at rest and during exercise and on flicker fusion
      frequency (FFF), FFF method evaluation

      Safety, tolerability and pharmacokinetics of cilobradine
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double
measure: Changes in heart rate at rest
time frame: Pre-dose, up to day 20 after first drug administration
measure: Changes in heart rate during exercise
time frame: Pre-dose, up to day 20 after first drug administration
measure: Changes in flicker fusion frequency test (FFF)
time frame: Pre-dose, up to day 20 after first drug administration
measure: Number of patients with clinically relevant changes in laboratory tests
time frame: Pre-dose, up to 12 days after last drug administration
measure: Number of patients with clinically relevant changes in vital signs (blood pressure, heart rate)
time frame: Pre-dose, up to 12 days after last drug administration
measure: Number of patients with clinically relevant changes in 12-lead ECG
time frame: Pre-dose, up to 12 days after last drug administration
measure: Number of patients with adverse events
time frame: Up to 12 days after last drug administration
measure: Assessment of global tolerability by the investigator
time frame: Up to 12 days after last drug administration
measure: Changes in peripheral FFF
time frame: Pre-dose, up to day 20 after first drug administration
measure: Area under the concentration-time curve of the analytes in plasma (AUC)
time frame: Up to day 20 after start of first drug administration
measure: Maximum measured concentration of the analytes in plasma (Cmax)
time frame: Up to day 20 after start of first drug administration
measure: Time from dosing to the maximum concentration of the analytes in plasma (tmax)
time frame: Up to day 20 after start of first drug administration
measure: Terminal half-life of the analytes in plasma (t½)
time frame: Up to day 20 after start of first drug administration
measure: Mean residence time of the analytes in the body after oral administration (MRTpo)
time frame: Up to day 20 after start of first drug administration
measure: Total clearance of the analytes in plasma following extravascular administration (CL/F)
time frame: Up to day 20 after start of first drug administration
measure: Apparent volume of distribution of the analytes during the terminal phase λz following extravascular administration (Vz/F)
time frame: Up to day 20 after start of first drug administration
arm group label: Cilobradine low dose 1
arm group type: Experimental
arm group label: Cilobradine low dose 2
arm group type: Experimental
arm group label: Cilobradine medium dose
arm group type: Experimental
arm group label: Cilobradine high dose 1
arm group type: Experimental
arm group label: Cilobradine high dose 2
arm group type: Experimental
arm group label: Metoprolol succinate
arm group type: Active Comparator
description: 1 tablet on day 1, day 2 followed by two tablets from day 3 to day 14
arm group label: Placebo
arm group type: Placebo Comparator
intervention type: Drug
intervention name: Cilobradine low dose 1
arm group label: Cilobradine low dose 1
intervention type: Drug
intervention name: Cilobradine low dose 2
arm group label: Cilobradine low dose 2
intervention type: Drug
intervention name: Cilobradine medium dose
arm group label: Cilobradine medium dose
intervention type: Drug
intervention name: Cilobradine high dose 1
arm group label: Cilobradine high dose 1
intervention type: Drug
intervention name: Cilobradine high dose 2
arm group label: Cilobradine high dose 2
intervention type: Drug
intervention name: Metoprolol succinate tablets
arm group label: Metoprolol succinate
intervention type: Drug
intervention name: Placebo
arm group label: Placebo
criteria: 
gender: All
minimum age: 21 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
url: http://trials.boehringer-ingelheim.com
description: Related Info
responsible party type: Sponsor
mesh term: Metoprolol