<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/NCT02224105</url>
  </required_header>
  <id_info>
    <org_study_id>1262.9</org_study_id>
    <nct_id>NCT02224105</nct_id>
  </id_info>
  <brief_title>Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of BI 653048 BS H3PO4 Capsule Assessing Endotoxin-induced Inflammatory Response in Healthy Male Subjects</brief_title>
  <official_title>Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of a BI 653048 BS H3PO4 Capsule Formulation Administered as Multiple Doses of 25 mg to 200 mg Once Daily (qd) for 3 Days Assessing Pharmacodynamics as Endotoxin-induced Inflammatory Response of a Single Intravenous Bolus Administration of 2 ng/kg Body Weight Lipopolysaccharide (LPS). A Randomised, Double-blind Within Dose Groups, Placebo-controlled, Multiple Rising Dose Phase I Trial With Open-label Active Comparator in Healthy Male Subjects</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Boehringer Ingelheim</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Boehringer Ingelheim</source>
  <brief_summary>
    <textblock>
      The general aim of the current study was to investigate the safety and tolerability, and&#xD;
      pharmacodynamics (endotoxin-induced inflammatory response of a single intravenous bolus&#xD;
      administration of 2 ng/kg body weight Escherichia coli lipopolysaccharide (LPS)) of BI 653048&#xD;
      BS H3PO4 capsules in healthy male subjects following oral administration of multiple rising&#xD;
      doses of 25 mg to 200 mg over three days compared to the active comparator prednisolone and&#xD;
      placebo.&#xD;
&#xD;
      Pharmacodynamics were assessed by investigating the influence of LPS administration on&#xD;
      inflammatory parameters. More specifically, it was evaluated whether and to what extent the&#xD;
      symptoms induced by LPS challenge can be attenuated by ascending BI 653048 BS H3PO4 doses&#xD;
      using prednisolone as positive control and placebo as negative control. A secondary objective&#xD;
      was the exploration of pharmacokinetics of BI 653048 BS, the investigation of other&#xD;
      pharmacodynamic parameters (biomarker) and of the tolerability of LPS.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>March 2010</start_date>
  <primary_completion_date type="Actual">May 2010</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>Number of subjects with adverse events</measure>
    <time_frame>up to 37 days</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of subjects with clinically significant findings in vital signs</measure>
    <time_frame>up to day 15</time_frame>
    <description>blood pressure, pulse rate and body temperature</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of subjects with clinically significant findings in 12-lead electrocardiogram (ECG)</measure>
    <time_frame>up to day 15</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of subjects with clinically significant findings in laboratory tests</measure>
    <time_frame>up to day 15</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Assessment of tolerability by investigator on a 4-point scale</measure>
    <time_frame>up to day 15</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum measured concentration of the biomarker level in plasma (Emax)</measure>
    <time_frame>up to 96 hours after first drug administration</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Area under the concentration-time curve of the biomarker in plasma over the time interval from 0 to the last measurable time point of the dose (AUEC)</measure>
    <time_frame>up to 96 hours after first drug administration</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Maximum measured concentration of the analyte in plasma at steady state (Cmax,ss)</measure>
    <time_frame>up to 96 hours after first drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time from dosing to maximum measured concentration of the analyte at steady state (tmax,ss)</measure>
    <time_frame>up to 96 hours after first drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the concentration-time curve of the analyte in the plasma over the time interval from 0 to the last measurable time point of the dose at steady state (AUC0-tz,ss)</measure>
    <time_frame>up to 96 hours after first drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity at steady state (AUC0-∞,ss)</measure>
    <time_frame>up to 96 hours after first drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of the AUC0-∞ that is obtained by extrapolation at steady state (%AUCtz-∞,ss)</measure>
    <time_frame>up to 96 hours after first drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Terminal phase elimination rate constant at steady state (λz,ss)</measure>
    <time_frame>up to 96 hours after first drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Terminal phase elimination half life at steady state (t1/2,ss)</measure>
    <time_frame>up to 96 hours after first drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mean residence time of the analyte in the body after oral administration at steady state (MRTpo,ss)</measure>
    <time_frame>up to 96 hours after first drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apparent clearance of the analyte in plasma following extravascular administration at steady state (CL/Fss)</measure>
    <time_frame>up to 96 hours after first drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apparent volume of distribution during the terminal phase λz following an extravascular dose at steady state (Vz/Fss)</measure>
    <time_frame>up to 96 hours after first drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Minimum measured concentration of the biomarker during the treatment interval (Emin)</measure>
    <time_frame>up to 96 hours after first drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the concentration-time curve of the biomarker in serum over the time interval from 0 to the last measurable time point of the dose (AUEC)</measure>
    <time_frame>up to 96 hours after first drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measured concentration of the biomarker at time t after the beginning of the treatment interval (Et)</measure>
    <time_frame>up to 96 hours after first drug administration</time_frame>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">56</enrollment>
  <condition>Healthy</condition>
  <arm_group>
    <arm_group_label>BI 653048 BS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>escalating doses</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Prednisolone low</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Prednisolone high</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
  </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>BI 653048 BS</intervention_name>
    <arm_group_label>BI 653048 BS</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prednisolone low</intervention_name>
    <arm_group_label>Prednisolone low</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prednisolone high</intervention_name>
    <arm_group_label>Prednisolone high</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>sodium chloride infusion</intervention_name>
    <arm_group_label>BI 653048 BS</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_label>Prednisolone high</arm_group_label>
    <arm_group_label>Prednisolone low</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>endotoxin escherichia coli (E. coli) lipopolysaccharide (LPS)</intervention_name>
    <arm_group_label>BI 653048 BS</arm_group_label>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_label>Prednisolone high</arm_group_label>
    <arm_group_label>Prednisolone low</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Healthy males according to the following criteria:&#xD;
&#xD;
             Based upon a complete medical history, including the physical examination, vital signs&#xD;
             (blood pressure, pulse rate and body temperature), 12-lead ECG, clinical laboratory&#xD;
             tests&#xD;
&#xD;
          2. Age ≥18 and Age ≤50 years&#xD;
&#xD;
          3. Body mass index (BMI) ≥18.5 and BMI ≤29.9 kg/m2&#xD;
&#xD;
          4. Signed and dated written informed consent prior to admission to the study in&#xD;
             accordance with Good Clinical Practice (GCP) and the local legislation&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Any finding of the medical examination (including blood pressure, pulse rate,&#xD;
             orthostatic test, body temperature and ECG) deviating from normal and of clinical&#xD;
             relevance&#xD;
&#xD;
          2. Any evidence of a clinically relevant concomitant disease&#xD;
&#xD;
          3. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic,&#xD;
             immunological or hormonal disorders&#xD;
&#xD;
          4. Surgery of the gastrointestinal tract (except appendectomy)&#xD;
&#xD;
          5. Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or&#xD;
             neurological disorders&#xD;
&#xD;
          6. History of relevant orthostatic hypotension, fainting spells or blackouts&#xD;
&#xD;
          7. Chronic or relevant acute infections&#xD;
&#xD;
          8. History of relevant allergy/hypersensitivity (including allergy to drug or its&#xD;
             excipients)&#xD;
&#xD;
          9. Intake of drugs with a long half-life (&gt;24 hours) within at least one month or less&#xD;
             than 10 half-lives of the respective drug prior to administration or during the trial&#xD;
&#xD;
         10. Use of drugs which might reasonably influence the results of the trial or that prolong&#xD;
             the QT/QTc interval based on the knowledge at the time of protocol preparation within&#xD;
             10 days prior to administration or during the trial&#xD;
&#xD;
         11. Participation in another trial with an investigational drug within 30 days prior to&#xD;
             administration or during the trial&#xD;
&#xD;
         12. Smoker (&gt;10 cigarettes or &gt;3 cigars or &gt;3 pipes/day)&#xD;
&#xD;
         13. Inability to refrain from smoking for 1 day prior to first drug administration until&#xD;
             discharge from the study site&#xD;
&#xD;
         14. Alcohol abuse (more than 60 g/day)&#xD;
&#xD;
         15. Drug abuse&#xD;
&#xD;
         16. Blood donation (more than 100 mL within four weeks prior to administration or during&#xD;
             the trial)&#xD;
&#xD;
         17. Excessive physical activities (within one week prior to administration or during the&#xD;
             trial)&#xD;
&#xD;
         18. Any laboratory value outside the reference range that is of clinical relevance&#xD;
&#xD;
         19. Inability to comply with dietary regimen of trial site&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>50 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>August 2014</verification_date>
  <study_first_submitted>August 21, 2014</study_first_submitted>
  <study_first_submitted_qc>August 21, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 25, 2014</study_first_posted>
  <last_update_submitted>August 21, 2014</last_update_submitted>
  <last_update_submitted_qc>August 21, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">August 25, 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>Prednisolone</mesh_term>
    <mesh_term>Methylprednisolone Acetate</mesh_term>
    <mesh_term>Methylprednisolone</mesh_term>
    <mesh_term>Methylprednisolone Hemisuccinate</mesh_term>
    <mesh_term>Prednisolone acetate</mesh_term>
    <mesh_term>Prednisolone hemisuccinate</mesh_term>
    <mesh_term>Prednisolone phosphate</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/NCT02224105
org study id: 1262.9
nct id: NCT02224105
lead sponsor: 
The general aim of the current study was to investigate the safety and tolerability, and
      pharmacodynamics (endotoxin-induced inflammatory response of a single intravenous bolus
      administration of 2 ng/kg body weight Escherichia coli lipopolysaccharide (LPS)) of BI 653048
      BS H3PO4 capsules in healthy male subjects following oral administration of multiple rising
      doses of 25 mg to 200 mg over three days compared to the active comparator prednisolone and
      placebo.

      Pharmacodynamics were assessed by investigating the influence of LPS administration on
      inflammatory parameters. More specifically, it was evaluated whether and to what extent the
      symptoms induced by LPS challenge can be attenuated by ascending BI 653048 BS H3PO4 doses
      using prednisolone as positive control and placebo as negative control. A secondary objective
      was the exploration of pharmacokinetics of BI 653048 BS, the investigation of other
      pharmacodynamic parameters (biomarker) and of the tolerability of LPS.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double
measure: Number of subjects with adverse events
time frame: up to 37 days
measure: Number of subjects with clinically significant findings in vital signs
time frame: up to day 15
description: blood pressure, pulse rate and body temperature
measure: Number of subjects with clinically significant findings in 12-lead electrocardiogram (ECG)
time frame: up to day 15
measure: Number of subjects with clinically significant findings in laboratory tests
time frame: up to day 15
measure: Assessment of tolerability by investigator on a 4-point scale
time frame: up to day 15
measure: Maximum measured concentration of the biomarker level in plasma (Emax)
time frame: up to 96 hours after first drug administration
measure: Area under the concentration-time curve of the biomarker in plasma over the time interval from 0 to the last measurable time point of the dose (AUEC)
time frame: up to 96 hours after first drug administration
measure: Maximum measured concentration of the analyte in plasma at steady state (Cmax,ss)
time frame: up to 96 hours after first drug administration
measure: Time from dosing to maximum measured concentration of the analyte at steady state (tmax,ss)
time frame: up to 96 hours after first drug administration
measure: Area under the concentration-time curve of the analyte in the plasma over the time interval from 0 to the last measurable time point of the dose at steady state (AUC0-tz,ss)
time frame: up to 96 hours after first drug administration
measure: Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity at steady state (AUC0-∞,ss)
time frame: up to 96 hours after first drug administration
measure: Percentage of the AUC0-∞ that is obtained by extrapolation at steady state (%AUCtz-∞,ss)
time frame: up to 96 hours after first drug administration
measure: Terminal phase elimination rate constant at steady state (λz,ss)
time frame: up to 96 hours after first drug administration
measure: Terminal phase elimination half life at steady state (t1/2,ss)
time frame: up to 96 hours after first drug administration
measure: Mean residence time of the analyte in the body after oral administration at steady state (MRTpo,ss)
time frame: up to 96 hours after first drug administration
measure: Apparent clearance of the analyte in plasma following extravascular administration at steady state (CL/Fss)
time frame: up to 96 hours after first drug administration
measure: Apparent volume of distribution during the terminal phase λz following an extravascular dose at steady state (Vz/Fss)
time frame: up to 96 hours after first drug administration
measure: Minimum measured concentration of the biomarker during the treatment interval (Emin)
time frame: up to 96 hours after first drug administration
measure: Area under the concentration-time curve of the biomarker in serum over the time interval from 0 to the last measurable time point of the dose (AUEC)
time frame: up to 96 hours after first drug administration
measure: Measured concentration of the biomarker at time t after the beginning of the treatment interval (Et)
time frame: up to 96 hours after first drug administration
arm group label: BI 653048 BS
arm group type: Experimental
description: escalating doses
arm group label: Prednisolone low
arm group type: Active Comparator
arm group label: Prednisolone high
arm group type: Active Comparator
arm group label: Placebo
arm group type: Placebo Comparator
intervention type: Drug
intervention name: BI 653048 BS
arm group label: BI 653048 BS
intervention type: Drug
intervention name: Prednisolone low
arm group label: Prednisolone low
intervention type: Drug
intervention name: Prednisolone high
arm group label: Prednisolone high
intervention type: Drug
intervention name: Placebo
arm group label: Placebo
intervention type: Drug
intervention name: sodium chloride infusion
arm group label: BI 653048 BS
arm group label: Placebo
arm group label: Prednisolone high
arm group label: Prednisolone low
intervention type: Drug
intervention name: endotoxin escherichia coli (E. coli) lipopolysaccharide (LPS)
arm group label: BI 653048 BS
arm group label: Placebo
arm group label: Prednisolone high
arm group label: Prednisolone low
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 50 Years
healthy volunteers: Accepts Healthy Volunteers
url: http://trials.boehringer-ingelheim.com
description: Related Info
responsible party type: Sponsor
mesh term: Prednisolone
mesh term: Methylprednisolone Acetate
mesh term: Methylprednisolone
mesh term: Methylprednisolone Hemisuccinate
mesh term: Prednisolone acetate
mesh term: Prednisolone hemisuccinate
mesh term: Prednisolone phosphate