<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/NCT02224521</url>
  </required_header>
  <id_info>
    <org_study_id>112071</org_study_id>
    <nct_id>NCT02224521</nct_id>
  </id_info>
  <brief_title>GSK2190915A - Bioavailability Study</brief_title>
  <official_title>An Open-label, Randomised, Single-dose, Multi-cohort, Crossover Bioavailability Study of a Solution Formulation and Three Capsule Formulations of GSK2190915 in Healthy Adult Subjects Followed by a Repeat-dose, Randomized, Parallel Group, Double-blinded Study of One Selected Capsule Formulation and Matched Placebo in Elderly Healthy Subjects</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>GlaxoSmithKline</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>GlaxoSmithKline</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      GSK2190915 is a high affinity 5-lipoxygenase-activating protein (FLAP) inhibitor that reduces&#xD;
      inflammation in cells.&#xD;
&#xD;
      This study will evaluate three capsule and two tablet formulations to select the optimal&#xD;
      formulation for further development. Safety will be assessed through clinical laboratory&#xD;
      testing, 12-lead electrocardiogram (ECG), vital signs and Adverse Event/ Serious Adverse&#xD;
      Event (AE/ SAE) recording.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      GSK2190915 is a high affinity 5-lipoxygenase-activating protein (FLAP) inhibitor that&#xD;
      attenuates the production of leukotrienes, through the blockage of the first committed step&#xD;
      in the leukotriene pathway, 5 lipoxygenase (5-LO) activation. Leukotrienes are potent&#xD;
      inflammatory molecules produced mainly by mast cells, eosinophils, monocytes/macrophage and&#xD;
      neutrophils in response to allergic or inflammatory stimuli.&#xD;
&#xD;
      Clinical studies conducted to date with GSK2190915 have utilised an aqueous formulation of&#xD;
      the compound. However, to progress the compound further in clinical development, a solid dose&#xD;
      formulation is necessary. This study will evaluate the optimal capsule formulation from a&#xD;
      selection of three available capsule formulations, and a dose, that can be taken forward for&#xD;
      future clinical development. Since it is expected that the compound will be developed for&#xD;
      Chronic Obstructive Pulmonary Disease (COPD), the study will also include a repeat-dose&#xD;
      cohort with elderly subjects (smokers and non-smokers over 65 years of age) in order to&#xD;
      evaluate the repeat-dose derived pharmacokinetic parameters of the selected capsule&#xD;
      formulation in this population.&#xD;
&#xD;
      This is a multi-cohort study and upto 6 cohorts will be performed.&#xD;
&#xD;
      In cohort 1, the bioavailability of single doses of 50 milligrammes (50 mg) of three capsule&#xD;
      formulations (capsule formulations A, B and C) in the fasted state will be assessed.&#xD;
      Depending on the bioavailability data obtained from cohort 1, one, two or three capsule&#xD;
      formulations may be taken forward into cohort 2.&#xD;
&#xD;
      If only one formulation is deemed to be suitable for progression, cohort 2 will be a&#xD;
      single-dose, 4-way complete crossover study to investigate both food-effect and dose&#xD;
      proportionality in 10 healthy adult subjects. The decision to progress this formulation to&#xD;
      the final (repeat-dose) cohort (cohort 4) will be made based on favourable food interaction&#xD;
      and proportionality in bioavailability between high and low doses in cohort 2.&#xD;
&#xD;
      If more than one capsule formulation fulfils the bioavailability criteria following cohort 1,&#xD;
      cohort 2 will be a food-effect study with a 100mg single dose of two or three selected&#xD;
      capsule formulations in healthy adult subjects. Progression to Cohort 3 will be dependent on&#xD;
      the formulation/s meeting predetermined pharmacokinetic (PK) criteria. Cohort 3 will be a&#xD;
      complete crossover study with single doses of 20mg and 200mg of each of upto two capsule&#xD;
      formulations taken forward from cohort 2 in 10 healthy adult subjects in the fasted state.&#xD;
      The aim of performing this cohort is to explore the dose proportionality between low and high&#xD;
      doses of the two selected capsule formulations.&#xD;
&#xD;
      Cohort 4 is a 12-day repeat-dose, double-blinded, placebo-controlled study in 12 healthy&#xD;
      elderly subjects (&gt;65 years) in the fed or fasted state with once-daily dosing of the highest&#xD;
      dose (200mg) of the capsule formulation (A, B or C) taken forward from the previous cohorts.&#xD;
      The aim of this cohort is to investigate the accumulation of the selected formulation during&#xD;
      repeat dosing.&#xD;
&#xD;
      Cohort 5 will be a 4-way complete crossover study with single doses of 100mg of two tablet&#xD;
      formulations (milled and micronised) administered to healthy volunteers in the fed and fasted&#xD;
      states. The aim of performing this cohort is to explore the single-dose pharmacokinetics of&#xD;
      the two tablet formulations with a view to assessing their suitability for use in subsequent&#xD;
      late- phase studies.&#xD;
&#xD;
      Cohort 6 will be a 4-way complete crossover study with single doses of 100mg of two modified&#xD;
      tablet formulations (different from Cohort 5 formulations) administered to healthy volunteers&#xD;
      in the fed and fasted states. The aim of performing this cohort is to explore the single-dose&#xD;
      pharmacokinetics of the two modified tablet formulations with a view to assessing their&#xD;
      suitability for use in subsequent late- phase studies.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 20, 2009</start_date>
  <completion_date type="Actual">June 8, 2010</completion_date>
  <primary_completion_date type="Actual">June 8, 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>Crossover Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Composite of plasma pharmacokinetic (PK) parameters of GSK2190915 in Cohort 1, 2 and 3</measure>
    <time_frame>PK samples will be collected at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48 and 72 hours post dose in each period up to 36 days</time_frame>
    <description>PK parameters including area under the plasma concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC [0-∞]), Area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration within a subject across all treatments (AUC[0-t]), concentrations at 24h post dose (C24), maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), terminal half-life (t1/2) and oral clearance (CL/F) for Cohort 1, 2, 3 will be measured.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Composite of PK parameters in Cohort 4</measure>
    <time_frame>Up to 12 days</time_frame>
    <description>PK parameters including area under the plasma concentration-time curve over the dosing interval (AUC [0-tau]), trough C24, Cmax, Tmax, and accumulation for Cohort 4 will be measured.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Composite of PK parameters in Cohort 5 and 6</measure>
    <time_frame>PK samples will be collected at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post dose in each period up to 36 days</time_frame>
    <description>PK parameters including AUC (0-∞), AUC (0-t), C24, Cmax, Tmax, t1/2 and CL/F for Cohort 5 and 6 will be measured.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Blood pressure measurement for Cohorts 1, 2, and 3 after GSK2190915 administration</measure>
    <time_frame>Up to 36 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood pressure measurement for Cohorts 4 after GSK2190915 administration</measure>
    <time_frame>Up to 12 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Blood pressure measurement for Cohorts 5 and 6 after GSK2190915 administration</measure>
    <time_frame>Up to 36 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pulse rate measurement for Cohorts 1, 2, and 3 after GSK2190915 administration</measure>
    <time_frame>Up to 36 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pulse rate measurement for Cohort 4 after GSK2190915 administration</measure>
    <time_frame>Up to 12 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pulse rate measurement for Cohorts 5 and 6 after GSK2190915 administration</measure>
    <time_frame>Up to 36 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ECG measurement for Cohorts 1, 2, 3 after GSK2190915 administration</measure>
    <time_frame>Up to 36 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ECG measurement for Cohort 4 after GSK2190915 administration</measure>
    <time_frame>Up to 12 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ECG measurement for Cohort 5 and 6 after GSK2190915 administration</measure>
    <time_frame>Up to 36 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Holter monitoring for Cohort 4 only after GSK2190915 administration</measure>
    <time_frame>Up to 12 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Laboratory assessment for Cohorts 1, 2, 3 after GSK2190915 administration</measure>
    <time_frame>Up to 36 days</time_frame>
    <description>Laboratory parameters including hematology, clinical chemistry, and urinalysis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Laboratory assessment for Cohort 4 after GSK2190915 administration</measure>
    <time_frame>Up to 12 days</time_frame>
    <description>Laboratory parameters including hematology, clinical chemistry, and urinalysis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Laboratory assessment for Cohort 5 and 6 after GSK2190915 administration</measure>
    <time_frame>Up to 36 days</time_frame>
    <description>Laboratory parameters including hematology, clinical chemistry, and urinalysis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse Event reporting for Cohorts 1, 2, and 3 after GSK2190915 administration</measure>
    <time_frame>Up to 36 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse Event reporting for Cohort 4 after GSK2190915 administration</measure>
    <time_frame>Up to 12 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse Event reporting for Cohorts 5 and 6 after GSK2190915 administration</measure>
    <time_frame>Up to 36 days</time_frame>
  </secondary_outcome>
  <number_of_arms>6</number_of_arms>
  <enrollment type="Actual">67</enrollment>
  <condition>Asthma</condition>
  <arm_group>
    <arm_group_label>Cohort 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will be assigned to any of the 4 dosage regimen (A, B, C, D) in four periods. A= GSK2190915 Solution, 50mg single dose, fasted; B = GSK2190915 Capsule Formulation A, 50mg single dose (1 x 50mg capsule), fasted; C= GSK2190915 Capsule Formulation B, 50mg single dose (1 x 50mg capsule), fasted; D= GSK2190915 Capsule Formulation C, 50mg single dose (1 x 50mg capsule), fasted.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The selected formulation will be dosed with GSK2190915 capsule formulation at 20mg (fasted), 100mg (fasted), 100mg (fed) and 200mg (fasted).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 3</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Cohort 3 will be a 4-way complete crossover study with single doses of 20mg and 200mg of up to two capsule formulations taken forward from cohort 2 in 10 healthy adult subjects in the fasted state.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 4</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The regimen for Cohort 4 will be either the highest dose (200mg) of the capsule formulation (A, B or C) taken forward from the previous cohorts or the solution formulation (200mg).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 5</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will take milled and micronised tablet formulations of GSK2190915 in the fasted state in periods 1 and 2, and will take milled and micronised tablet formulations of GS2190915 in the fed state in periods 3 and 4.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 6</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Tablet formulations (milled and micronised, different to the Cohort 5 formulations) of GSK2190915 will be dosed in the fasted and fed (after a light breakfast) states.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>GSK2190915 Solution.</intervention_name>
    <description>Aqueous Solution, 10mg/mL.</description>
    <arm_group_label>Cohort 1</arm_group_label>
    <arm_group_label>Cohort 2</arm_group_label>
    <arm_group_label>Cohort 3</arm_group_label>
    <arm_group_label>Cohort 4</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>GSK2190915 Granule Capsule (A)</intervention_name>
    <description>GSK2190915A granule filled in to Gelatin capsules</description>
    <arm_group_label>Cohort 1</arm_group_label>
    <arm_group_label>Cohort 2</arm_group_label>
    <arm_group_label>Cohort 3</arm_group_label>
    <arm_group_label>Cohort 4</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>GSK2190915 Semi-solid Lipid Capsule (B)</intervention_name>
    <description>GSK2190915A dispersed in a lipid vehicle and filled in to HPMC capsules</description>
    <arm_group_label>Cohort 1</arm_group_label>
    <arm_group_label>Cohort 2</arm_group_label>
    <arm_group_label>Cohort 3</arm_group_label>
    <arm_group_label>Cohort 4</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>GSK2190915 Liquid Lipid Capsule (C)</intervention_name>
    <description>GSK2190915A dissolved in lipid vehicle milled and filled in to Gelatin capsules</description>
    <arm_group_label>Cohort 1</arm_group_label>
    <arm_group_label>Cohort 2</arm_group_label>
    <arm_group_label>Cohort 3</arm_group_label>
    <arm_group_label>Cohort 4</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>GSK2190915 Milled Tablet</intervention_name>
    <description>GSK2190915A granule is blended, compressed into tablets and aqueous film coated</description>
    <arm_group_label>Cohort 5</arm_group_label>
    <arm_group_label>Cohort 6</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>GSK2190915 Micronised Tablet</intervention_name>
    <description>GSK2190915A granule is blended, compressed into tablets and aqueous film coated</description>
    <arm_group_label>Cohort 5</arm_group_label>
    <arm_group_label>Cohort 6</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        INCLUSION CRITERIA FOR COHORTS 1, 2, 3, 5 and 6.&#xD;
&#xD;
        A subject will be eligible for inclusion in cohorts 1, 2, 3, 5 and 6 of this study only if&#xD;
        all of the following criteria apply:&#xD;
&#xD;
          1. Aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase and&#xD;
             bilirubin less than or equal to 1.5 times Upper Limit of Normal, ULN (isolated&#xD;
             bilirubin &gt;1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin&#xD;
             less than 35 percent).&#xD;
&#xD;
          2. Healthy as determined by the Investigator, based on a medical evaluation including&#xD;
             medical history, physical examination, laboratory tests and Electrocardiogram (ECG). A&#xD;
             subject with a clinical abnormality or laboratory parameters outside the reference&#xD;
             range for the population being studied may be included only if the Investigator and&#xD;
             the GSK Medical Monitor agree that the finding is unlikely to introduce additional&#xD;
             risk factors and will not interfere with the study objectives.&#xD;
&#xD;
          3. Male or female (of non child-bearing potential) between 18 and 65 years of age&#xD;
             inclusive, at the time of signing the informed consent.&#xD;
&#xD;
             A female subject is eligible to participate only if she is of:&#xD;
&#xD;
             •Non-childbearing potential defined as pre-menopausal females with a documented tubal&#xD;
             ligation (in which case the male partner should use an acceptable form of&#xD;
             contraception as specified in section 8.1) or hysterectomy; or postmenopausal defined&#xD;
             as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with&#xD;
             simultaneous follicle stimulating hormone (FSH) &gt; 40 million international units,&#xD;
             MlU/ml and estradiol less than 40 picogrammes per millilitre (less than 140 picomoles&#xD;
             per litre) is confirmatory]. [Females on hormone replacement therapy (HRT) and whose&#xD;
             menopausal status is in doubt will be required to use one of the contraception methods&#xD;
             in Section 8.1 if they wish to continue their HRT during the study. Otherwise, they&#xD;
             must discontinue HRT to allow confirmation of post-menopausal status prior to study&#xD;
             enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the&#xD;
             cessation of therapy and the blood draw; this interval depends on the type and dosage&#xD;
             of HRT. Following confirmation of their post-menopausal status, they can resume use of&#xD;
             HRT during the study without use of a contraceptive method.]&#xD;
&#xD;
          4. Male subjects must agree to use one of the contraception methods listed in Section&#xD;
             8.1. This criterion must be followed from the time of the first dose of study&#xD;
             medication until 5 terminal half-lives post-last dose.&#xD;
&#xD;
          5. Capable of giving written informed consent, which includes compliance with the&#xD;
             requirements and restrictions listed in the consent form.&#xD;
&#xD;
        6.12 lead ECG without any clinically significant abnormality as judged by the Investigator,&#xD;
        and QTc intervals corrected for Bazett ror Fredericia (QTcB and QTcF) less than450&#xD;
        milliseconds (msec)&#xD;
&#xD;
        7.Body weight greater than or equal to 50 kilogrammes (kg) (110 pounds, lbs) for men and&#xD;
        greater than or equal to 45 kg (99 lbs) for women and Body Mass Index, BMI within the range&#xD;
        18-30 kilogrammes per squared metre (kg/m2) inclusive.&#xD;
&#xD;
        8.Non-smokers only- Negative urine cotinine test at screening, no history of smoking within&#xD;
        6 months of the start of the study, and with a total pack year history of less than or&#xD;
        equal to 1 pack years.&#xD;
&#xD;
        INCLUSION CRITERIA FOR COHORT 4&#xD;
&#xD;
        A subject will be eligible for inclusion in cohort 4 of this study only if all of the&#xD;
        following criteria apply:&#xD;
&#xD;
          1. Healthy as determined by the Investigator, based on a medical evaluation including&#xD;
             medical history, physical examination, laboratory tests, ECG and Holter assessment at&#xD;
             screening. A subject with a clinical abnormality or laboratory parameter outside the&#xD;
             reference range for the population being studied may be included only if the&#xD;
             Investigator and the GSK Medical Monitor agree that the finding is unlikely to&#xD;
             introduce additional risk factors and will not interfere with the study objectives. A&#xD;
             subject with a well controlled or mild medical condition (eg controlled hypertension,&#xD;
             hypothyroidism adequately treated with replacement therapy, mild chronic obstructive&#xD;
             pulmonary disease (COPD) requiring short acting bronchodilators only) may be included&#xD;
             only if the Investigator and the GSK Medical Monitor agree that the condition is&#xD;
             unlikely to introduce additional risk factors and will not interfere with the study&#xD;
             objectives.&#xD;
&#xD;
          2. Male or female (of non child-bearing potential) over 65 years of age inclusive, at the&#xD;
             time of signing the informed consent.&#xD;
&#xD;
             A female subject is eligible to participate only if she is of:&#xD;
&#xD;
             •Non-childbearing potential defined as pre-menopausal females with a documented tubal&#xD;
             ligation (in which case the male partner should use an acceptable form of&#xD;
             contraception as specified in section 8.1) or hysterectomy; or postmenopausal defined&#xD;
             as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with&#xD;
             simultaneous follicle stimulating hormone (FSH) &gt; 40 million international units,&#xD;
             MlU/ml and estradiol less than 40 picogrammes per millilitre (less than 140 picomoles&#xD;
             per litre) is confirmatory]. [Females on hormone replacement therapy (HRT) and whose&#xD;
             menopausal status is in doubt will be required to use one of the contraception methods&#xD;
             in Section 8.1 if they wish to continue their HRT during the study. Otherwise, they&#xD;
             must discontinue HRT to allow confirmation of post-menopausal status prior to study&#xD;
             enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the&#xD;
             cessation of therapy and the blood draw; this interval depends on the type and dosage&#xD;
             of HRT. Following confirmation of their post-menopausal status, they can resume use of&#xD;
             HRT during the study without use of a contraceptive method.]&#xD;
&#xD;
          3. Male subjects must agree to use one of the contraception methods listed in Section&#xD;
             8.1. This criterion must be followed from the time of the first dose of study&#xD;
             medication until 5 terminal half-lives post-last dose.&#xD;
&#xD;
          4. Capable of giving written informed consent, which includes compliance with the&#xD;
             requirements and restrictions listed in the consent form.&#xD;
&#xD;
        5.12 lead ECG without any clinically significant abnormality as judged by the Investigator&#xD;
        and QTcB and QTcF less than 450 msec&#xD;
&#xD;
        6.Body weight greater than or equal to 50 kg (110 lbs) for men and greater than or equal to&#xD;
        45 kg (99lbs) for women and BMI within the range 18-35 kg/m2 inclusive.&#xD;
&#xD;
        7.For non-smokers only - negative urine cotinine test at screening, no history of smoking&#xD;
        within 6 months of the start of the study, and with a total pack year history of less than&#xD;
        or equal to 1 pack years.&#xD;
&#xD;
        8.For smokers only - a smoking history of greater than or equal to 5 pack years and&#xD;
        currently smoking at least 5 cigarettes/day for the last 6 months&#xD;
&#xD;
        EXCLUSION CRITERIA&#xD;
&#xD;
        A subject will not be eligible for inclusion in this study if any of the following criteria&#xD;
        apply:&#xD;
&#xD;
          1. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody&#xD;
             result within 3 months of screening&#xD;
&#xD;
          2. Current or chronic history of liver disease, or known hepatic or biliary abnormalities&#xD;
             (with the exception of Gilbert's syndrome or asymptomatic gallstones).&#xD;
&#xD;
          3. Significant cardiac, pulmonary, metabolic, renal, gastrointestinal or other conditions&#xD;
             that in the opinion of the investigator and/or GSK medical monitor, places the subject&#xD;
             at an unacceptable risk as participant in this trial.&#xD;
&#xD;
          4. A positive pre-study drug/alcohol screen.&#xD;
&#xD;
          5. A positive test for human immunodeficiency virus (HIV) antibody.&#xD;
&#xD;
          6. History of regular alcohol consumption within 6 months of the study defined as an&#xD;
             average weekly intake of greater than 21 units for males or less than14 units for&#xD;
             females. One unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1&#xD;
             glass (125 ml) of wine or 1 (25 ml) measure of spirits.&#xD;
&#xD;
          7. The subject has participated in a clinical trial and has received an investigational&#xD;
             product within the following time period prior to the first dosing day in the current&#xD;
             study: 3 months or 5 half-lives or twice the duration of the biological effect of the&#xD;
             investigational product (whichever is longer).&#xD;
&#xD;
          8. Exposure to more than four new chemical entities within 12 months prior to the first&#xD;
             dosing day.&#xD;
&#xD;
          9. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary&#xD;
             supplements (including St John's Wort) within 7 days (or 14 days if the drug is a&#xD;
             potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first&#xD;
             dose of study medication, unless in the opinion of the Investigator and GSK Medical&#xD;
             Monitor the medication will not interfere with the study procedures or compromise&#xD;
             subject safety.&#xD;
&#xD;
         10. History of sensitivity to any of the study medications, or components thereof or a&#xD;
             history of drug or other allergy that, in the opinion of the investigator or GSK&#xD;
             Medical Monitor, contraindicates their participation.&#xD;
&#xD;
         11. Where participation in the study would result in donation of blood or blood products&#xD;
             in excess of 500 mL within a 56 day period.&#xD;
&#xD;
         12. Pregnant females as determined by positive serum or urine human Chorionic&#xD;
             Gonadotrophin (hCG) test at screening or prior to dosing.&#xD;
&#xD;
         13. Lactating females.&#xD;
&#xD;
         14. Unwillingness or inability to follow the procedures outlined in the protocol.&#xD;
&#xD;
         15. Subject is mentally or legally incapacitated.&#xD;
&#xD;
         16. Consumption of red wine, seville oranges, grapefruit or grapefruit juice and/or&#xD;
             pummelos, exotic citrus fruits, grapefruit hybrids or fruit juices from 7 days prior&#xD;
             to the first dose of study medication.&#xD;
&#xD;
         17. For non-smokers only - urinary cotinine levels indicative of smoking or history or&#xD;
             regular use of tobacco- or nicotine-containing products within 6 months prior to&#xD;
             screening.&#xD;
&#xD;
         18. Blood pressure persistently greater than 150 over 90 (150/90) millimetres of mercury&#xD;
             (mmHg) at screening.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>GSK Clinical Trials</last_name>
    <role>Study Director</role>
    <affiliation>GlaxoSmithKline</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>GSK Investigational Site</name>
      <address>
        <city>London</city>
        <zip>NW10 7EW</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <link>
    <url>https://www.clinicalstudydatarequest.com</url>
    <description>Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.</description>
  </link>
  <verification_date>June 2017</verification_date>
  <study_first_submitted>June 23, 2011</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>June 13, 2017</last_update_submitted>
  <last_update_submitted_qc>June 13, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">June 14, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>FLAP inhibitor</keyword>
  <keyword>Chronic Obstructive Pulmonary Disease (COPD)</keyword>
  <keyword>COPD</keyword>
  <keyword>Bioavailability</keyword>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.</ipd_description>
  </patient_data>
  <study_docs>
    <study_doc>
      <doc_id>112071</doc_id>
      <doc_type>Clinical Study Report</doc_type>
      <doc_url>https://www.clinicalstudydatarequest.com</doc_url>
      <doc_comment>For additional information about this study please refer to the GSK Clinical Study Register</doc_comment>
    </study_doc>
    <study_doc>
      <doc_id>112071</doc_id>
      <doc_type>Study Protocol</doc_type>
      <doc_url>https://www.clinicalstudydatarequest.com</doc_url>
      <doc_comment>For additional information about this study please refer to the GSK Clinical Study Register</doc_comment>
    </study_doc>
    <study_doc>
      <doc_id>112071</doc_id>
      <doc_type>Annotated Case Report Form</doc_type>
      <doc_url>https://www.clinicalstudydatarequest.com</doc_url>
      <doc_comment>For additional information about this study please refer to the GSK Clinical Study Register</doc_comment>
    </study_doc>
    <study_doc>
      <doc_id>112071</doc_id>
      <doc_type>Informed Consent Form</doc_type>
      <doc_url>https://www.clinicalstudydatarequest.com</doc_url>
      <doc_comment>For additional information about this study please refer to the GSK Clinical Study Register</doc_comment>
    </study_doc>
    <study_doc>
      <doc_id>112071</doc_id>
      <doc_type>Individual Participant Data Set</doc_type>
      <doc_url>https://www.clinicalstudydatarequest.com</doc_url>
      <doc_comment>For additional information about this study please refer to the GSK Clinical Study Register</doc_comment>
    </study_doc>
    <study_doc>
      <doc_id>112071</doc_id>
      <doc_type>Dataset Specification</doc_type>
      <doc_url>https://www.clinicalstudydatarequest.com</doc_url>
      <doc_comment>For additional information about this study please refer to the GSK Clinical Study Register</doc_comment>
    </study_doc>
    <study_doc>
      <doc_id>112071</doc_id>
      <doc_type>Statistical Analysis Plan</doc_type>
      <doc_url>https://www.clinicalstudydatarequest.com</doc_url>
      <doc_comment>For additional information about this study please refer to the GSK Clinical Study Register</doc_comment>
    </study_doc>
  </study_docs>
  <!-- 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/NCT02224521
org study id: 112071
nct id: NCT02224521
lead sponsor: 
has dmc: No
GSK2190915 is a high affinity 5-lipoxygenase-activating protein (FLAP) inhibitor that reduces
      inflammation in cells.

      This study will evaluate three capsule and two tablet formulations to select the optimal
      formulation for further development. Safety will be assessed through clinical laboratory
      testing, 12-lead electrocardiogram (ECG), vital signs and Adverse Event/ Serious Adverse
      Event (AE/ SAE) recording.
GSK2190915 is a high affinity 5-lipoxygenase-activating protein (FLAP) inhibitor that
      attenuates the production of leukotrienes, through the blockage of the first committed step
      in the leukotriene pathway, 5 lipoxygenase (5-LO) activation. Leukotrienes are potent
      inflammatory molecules produced mainly by mast cells, eosinophils, monocytes/macrophage and
      neutrophils in response to allergic or inflammatory stimuli.

      Clinical studies conducted to date with GSK2190915 have utilised an aqueous formulation of
      the compound. However, to progress the compound further in clinical development, a solid dose
      formulation is necessary. This study will evaluate the optimal capsule formulation from a
      selection of three available capsule formulations, and a dose, that can be taken forward for
      future clinical development. Since it is expected that the compound will be developed for
      Chronic Obstructive Pulmonary Disease (COPD), the study will also include a repeat-dose
      cohort with elderly subjects (smokers and non-smokers over 65 years of age) in order to
      evaluate the repeat-dose derived pharmacokinetic parameters of the selected capsule
      formulation in this population.

      This is a multi-cohort study and upto 6 cohorts will be performed.

      In cohort 1, the bioavailability of single doses of 50 milligrammes (50 mg) of three capsule
      formulations (capsule formulations A, B and C) in the fasted state will be assessed.
      Depending on the bioavailability data obtained from cohort 1, one, two or three capsule
      formulations may be taken forward into cohort 2.

      If only one formulation is deemed to be suitable for progression, cohort 2 will be a
      single-dose, 4-way complete crossover study to investigate both food-effect and dose
      proportionality in 10 healthy adult subjects. The decision to progress this formulation to
      the final (repeat-dose) cohort (cohort 4) will be made based on favourable food interaction
      and proportionality in bioavailability between high and low doses in cohort 2.

      If more than one capsule formulation fulfils the bioavailability criteria following cohort 1,
      cohort 2 will be a food-effect study with a 100mg single dose of two or three selected
      capsule formulations in healthy adult subjects. Progression to Cohort 3 will be dependent on
      the formulation/s meeting predetermined pharmacokinetic (PK) criteria. Cohort 3 will be a
      complete crossover study with single doses of 20mg and 200mg of each of upto two capsule
      formulations taken forward from cohort 2 in 10 healthy adult subjects in the fasted state.
      The aim of performing this cohort is to explore the dose proportionality between low and high
      doses of the two selected capsule formulations.

      Cohort 4 is a 12-day repeat-dose, double-blinded, placebo-controlled study in 12 healthy
      elderly subjects (>65 years) in the fed or fasted state with once-daily dosing of the highest
      dose (200mg) of the capsule formulation (A, B or C) taken forward from the previous cohorts.
      The aim of this cohort is to investigate the accumulation of the selected formulation during
      repeat dosing.

      Cohort 5 will be a 4-way complete crossover study with single doses of 100mg of two tablet
      formulations (milled and micronised) administered to healthy volunteers in the fed and fasted
      states. The aim of performing this cohort is to explore the single-dose pharmacokinetics of
      the two tablet formulations with a view to assessing their suitability for use in subsequent
      late- phase studies.

      Cohort 6 will be a 4-way complete crossover study with single doses of 100mg of two modified
      tablet formulations (different from Cohort 5 formulations) administered to healthy volunteers
      in the fed and fasted states. The aim of performing this cohort is to explore the single-dose
      pharmacokinetics of the two modified tablet formulations with a view to assessing their
      suitability for use in subsequent late- phase studies.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Other
masking: None (Open Label)
measure: Composite of plasma pharmacokinetic (PK) parameters of GSK2190915 in Cohort 1, 2 and 3
time frame: PK samples will be collected at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48 and 72 hours post dose in each period up to 36 days
description: PK parameters including area under the plasma concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC [0-∞]), Area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration within a subject across all treatments (AUC[0-t]), concentrations at 24h post dose (C24), maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), terminal half-life (t1/2) and oral clearance (CL/F) for Cohort 1, 2, 3 will be measured.
measure: Composite of PK parameters in Cohort 4
time frame: Up to 12 days
description: PK parameters including area under the plasma concentration-time curve over the dosing interval (AUC [0-tau]), trough C24, Cmax, Tmax, and accumulation for Cohort 4 will be measured.
measure: Composite of PK parameters in Cohort 5 and 6
time frame: PK samples will be collected at pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post dose in each period up to 36 days
description: PK parameters including AUC (0-∞), AUC (0-t), C24, Cmax, Tmax, t1/2 and CL/F for Cohort 5 and 6 will be measured.
measure: Blood pressure measurement for Cohorts 1, 2, and 3 after GSK2190915 administration
time frame: Up to 36 days
measure: Blood pressure measurement for Cohorts 4 after GSK2190915 administration
time frame: Up to 12 days
measure: Blood pressure measurement for Cohorts 5 and 6 after GSK2190915 administration
time frame: Up to 36 days
measure: Pulse rate measurement for Cohorts 1, 2, and 3 after GSK2190915 administration
time frame: Up to 36 days
measure: Pulse rate measurement for Cohort 4 after GSK2190915 administration
time frame: Up to 12 days
measure: Pulse rate measurement for Cohorts 5 and 6 after GSK2190915 administration
time frame: Up to 36 days
measure: ECG measurement for Cohorts 1, 2, 3 after GSK2190915 administration
time frame: Up to 36 days
measure: ECG measurement for Cohort 4 after GSK2190915 administration
time frame: Up to 12 days
measure: ECG measurement for Cohort 5 and 6 after GSK2190915 administration
time frame: Up to 36 days
measure: Holter monitoring for Cohort 4 only after GSK2190915 administration
time frame: Up to 12 days
measure: Laboratory assessment for Cohorts 1, 2, 3 after GSK2190915 administration
time frame: Up to 36 days
description: Laboratory parameters including hematology, clinical chemistry, and urinalysis
measure: Laboratory assessment for Cohort 4 after GSK2190915 administration
time frame: Up to 12 days
description: Laboratory parameters including hematology, clinical chemistry, and urinalysis
measure: Laboratory assessment for Cohort 5 and 6 after GSK2190915 administration
time frame: Up to 36 days
description: Laboratory parameters including hematology, clinical chemistry, and urinalysis
measure: Adverse Event reporting for Cohorts 1, 2, and 3 after GSK2190915 administration
time frame: Up to 36 days
measure: Adverse Event reporting for Cohort 4 after GSK2190915 administration
time frame: Up to 12 days
measure: Adverse Event reporting for Cohorts 5 and 6 after GSK2190915 administration
time frame: Up to 36 days
arm group label: Cohort 1
arm group type: Experimental
description: Subjects will be assigned to any of the 4 dosage regimen (A, B, C, D) in four periods. A= GSK2190915 Solution, 50mg single dose, fasted; B = GSK2190915 Capsule Formulation A, 50mg single dose (1 x 50mg capsule), fasted; C= GSK2190915 Capsule Formulation B, 50mg single dose (1 x 50mg capsule), fasted; D= GSK2190915 Capsule Formulation C, 50mg single dose (1 x 50mg capsule), fasted.
arm group label: Cohort 2
arm group type: Experimental
description: The selected formulation will be dosed with GSK2190915 capsule formulation at 20mg (fasted), 100mg (fasted), 100mg (fed) and 200mg (fasted).
arm group label: Cohort 3
arm group type: Experimental
description: Cohort 3 will be a 4-way complete crossover study with single doses of 20mg and 200mg of up to two capsule formulations taken forward from cohort 2 in 10 healthy adult subjects in the fasted state.
arm group label: Cohort 4
arm group type: Experimental
description: The regimen for Cohort 4 will be either the highest dose (200mg) of the capsule formulation (A, B or C) taken forward from the previous cohorts or the solution formulation (200mg).
arm group label: Cohort 5
arm group type: Experimental
description: Subjects will take milled and micronised tablet formulations of GSK2190915 in the fasted state in periods 1 and 2, and will take milled and micronised tablet formulations of GS2190915 in the fed state in periods 3 and 4.
arm group label: Cohort 6
arm group type: Experimental
description: Tablet formulations (milled and micronised, different to the Cohort 5 formulations) of GSK2190915 will be dosed in the fasted and fed (after a light breakfast) states.
intervention type: Drug
intervention name: GSK2190915 Solution.
description: Aqueous Solution, 10mg/mL.
arm group label: Cohort 1
arm group label: Cohort 2
arm group label: Cohort 3
arm group label: Cohort 4
intervention type: Drug
intervention name: GSK2190915 Granule Capsule (A)
description: GSK2190915A granule filled in to Gelatin capsules
arm group label: Cohort 1
arm group label: Cohort 2
arm group label: Cohort 3
arm group label: Cohort 4
intervention type: Drug
intervention name: GSK2190915 Semi-solid Lipid Capsule (B)
description: GSK2190915A dispersed in a lipid vehicle and filled in to HPMC capsules
arm group label: Cohort 1
arm group label: Cohort 2
arm group label: Cohort 3
arm group label: Cohort 4
intervention type: Drug
intervention name: GSK2190915 Liquid Lipid Capsule (C)
description: GSK2190915A dissolved in lipid vehicle milled and filled in to Gelatin capsules
arm group label: Cohort 1
arm group label: Cohort 2
arm group label: Cohort 3
arm group label: Cohort 4
intervention type: Drug
intervention name: GSK2190915 Milled Tablet
description: GSK2190915A granule is blended, compressed into tablets and aqueous film coated
arm group label: Cohort 5
arm group label: Cohort 6
intervention type: Drug
intervention name: GSK2190915 Micronised Tablet
description: GSK2190915A granule is blended, compressed into tablets and aqueous film coated
arm group label: Cohort 5
arm group label: Cohort 6
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: GSK Clinical Trials
role: Study Director
affiliation: GlaxoSmithKline
facility: 
country: United Kingdom
url: https://www.clinicalstudydatarequest.com
description: Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.
responsible party type: Sponsor
sharing ipd: Yes
ipd description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
study doc: 
study doc: 
study doc: 
study doc: 
study doc: 
study doc: 
study doc: 