<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/NCT01725139</url>
  </required_header>
  <id_info>
    <org_study_id>116711</org_study_id>
    <secondary_id>2012-001376-11</secondary_id>
    <nct_id>NCT01725139</nct_id>
  </id_info>
  <brief_title>A Proof of Mechanism Study With GSK2126458 in Patients With Idiopathic Pulmonary Fibrosis (IPF)</brief_title>
  <official_title>A Randomised, Placebo-controlled, Double-blind, Repeat Dose Escalation Study With GSK2126458 in Patients With Idiopathic Pulmonary Fibrosis (IPF)</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>
      This is a dose escalation/dose finding, double-blind, placebo-controlled, parallel study of&#xD;
      GSK2126458 in subjects with IPF. The study is designed to explore a number of doses of&#xD;
      GSK2126458 for engagement of pharmacology after short term dosing. It is anticipated that&#xD;
      approximately 24 subjects will be enrolled in this study. Actual number of cohorts in this&#xD;
      study could vary up to a maximum of 6 cohorts (n=4/cohort; 3 on active and 1 on placebo).&#xD;
&#xD;
      Each cohort will consist of four subjects who will be randomised to receive GSK2126458 (three&#xD;
      subjects) or placebo (one subject) for approximately 8 days (7 to 10 days). On Day 1 they&#xD;
      will receive their first dose of GSK2126458 (or placebo) and safety, tolerability and PK/PD&#xD;
      in the blood will be measured for up to 8 hours post-dose. Subjects will then be discharged&#xD;
      from the site with study drug until the last day of dosing. They will also receive hand held&#xD;
      spirometers and instructions on action to be taken in case of deterioration in pulmonary&#xD;
      function or any other adverse events (AEs). On the last day of dosing they will return to the&#xD;
      site for a repeat of the Day 1 procedures.&#xD;
&#xD;
      A bronchoalveolar lavage (BAL) and [18F]-fluoro-deoxyglucose (FDG)- positron emission&#xD;
      tomography / computed tomography (PET/CT) scan will be conducted twice during the study;&#xD;
      once, at least 2 days before dosing commences and again during the course of the dosing&#xD;
      period.&#xD;
&#xD;
      After the final subject in each cohort has completed dosing, a dose escalation meeting will&#xD;
      take place. Safety and tolerability and PK data will be reviewed during this meeting and&#xD;
      decisions made may include but are not limited to: escalate the dose, decrease the dose or&#xD;
      repeat the same dose in the next cohort; stop the study.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 8, 2013</start_date>
  <completion_date type="Actual">July 12, 2016</completion_date>
  <primary_completion_date type="Actual">July 12, 2016</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 (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Pharmacodynamic (PD) endpoints pAKT/AKT in platelet-rich plasma and BAL cells, [18F]-FDG-PET/CT</measure>
    <time_frame>Baseline, Day 1, mid-study BAL visit (Day 5-9) and final dosing day (Day 7, 8, 9 or 10) for each cohort</time_frame>
    <description>Pharmacodynamic will be measured by inhibition of pAKT/AKT in platelet-rich plasma and BAL cells, as well as inhibition of glucose uptake as measured by thoracic[18F]-FDG-PET/CT</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area under the curve (AUC) in blood for GSK2126458</measure>
    <time_frame>Day 1, mid-study PET visit (Day 4-8), mid-study BAL visit (Day 5-9) and final dosing day post-dose (Day 7, 8, 9 or 10) for each cohort</time_frame>
    <description>GSK2126458 PK parameters in blood in order to define the blood and pulmonary PK/PD relationship for GSK2126458 in IPF subjects</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum observed concentration (Cmax) in blood for GSK2126458</measure>
    <time_frame>Day 1, mid-study PET visit (Day 4-8), mid-study BAL visit (Day 5-9) and final dosing day post-dose (Day 7, 8, 9 or 10) for each cohort</time_frame>
    <description>GSK2126458 PK parameters in blood in order to define the blood and pulmonary PK/PD relationship for GSK2126458 in IPF subjects</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pre-dose (trough) concentration at the end of the dosing interval (Ctrough) in blood for GSK2126458</measure>
    <time_frame>Day 1, mid-study PET visit (Day 4-8), mid-study BAL visit (Day 5-9) and final dosing day post-dose (Day 7, 8, 9 or 10) for each cohort</time_frame>
    <description>GSK2126458 PK parameters in blood in order to define the blood and pulmonary PK/PD relationship for GSK2126458 in IPF subjects</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Concentration of GSK2126458 in bronchoalveolar lavage fluid (BALF)</measure>
    <time_frame>Baseline BAL visit and mid-study BAL visit (Day 5-9).</time_frame>
    <description>GSK2126458 concentration in BALF in order to define the pulmonary PK/PD relationship for GSK2126458 in IPF subjects</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety and tolerability of GSK2126458 as assessed by number of subjects with adverse events (AE)s</measure>
    <time_frame>Baseline up to final dosing day (Day 7, 8, 9 or 10) for each cohort</time_frame>
    <description>Safety and tolerability parameters will include recording of AEs, throughout the study in subjects with IPF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety and tolerability of GSK2126458 as assessed by change from baseline in vital signs</measure>
    <time_frame>Day 1, final dosing day (Day 7, 8, 9 or 10) and follow-up (10-14 days post last dose), for each cohort</time_frame>
    <description>Vital sign measurement will be done in a semi-supine position and will include systolic and diastolic blood pressure, pulse rate and tympanic temperature</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety and tolerability of GSK2126458 as assessed by change from baseline in clinical laboratory parameters</measure>
    <time_frame>Day 1, mid-study BAL visit (Day 5-9), final dosing day (Day 7, 8, 9 or 10) and follow-up (10-14 days post last dose) for each cohort</time_frame>
    <description>Clinical laboratory assessments will include haematology, clinical chemistry, urinalysis and additional parameters</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety and tolerability of GSK2126458 as assessed by change from baseline in pulmonary function</measure>
    <time_frame>Recorded daily from screening until final dosing day (Day 7, 8, 9 or 10) for each cohort</time_frame>
    <description>Pulmonary function will be assessed by spirometry to test the forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety and tolerability of GSK2126458 as assessed by change from baseline in electrocardiogram (ECG)</measure>
    <time_frame>Screening, Day 1 and final dosing day (Day 7, 8, 9 or 10) for each study cohort</time_frame>
    <description>Single 12-lead ECG will be obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT and QTc intervals</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of subject's breathlessness using MRC dyspnoea scale</measure>
    <time_frame>Day 1 and final dosing day (Day 7, 8, 9 or 10) for each study cohort</time_frame>
    <description>The Medical Research Council (MRC) dyspnoea scale is a 5-point scale used for grading the degree of a patient's breathlessness.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of FEV1 and FVC using daily hand-held spirometry</measure>
    <time_frame>Recorded daily from screening until final dosing day (Day 7, 8, 9 or 10) for each cohort</time_frame>
    <description>Subjects will be required to record their daily spirometry scores (FEV1 and FVC) using hand-held spirometers, at approximately the same time each morning between Screening and the Final Dosing Day</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Investigate the effect of GSK2126458 on the frequency and or severity of chronic cough using Leicester Cough Questionnaire (LCQ) in IPF subjects</measure>
    <time_frame>Day 1 and final dosing day (Day 7, 8, 9 or 10) for each cohort</time_frame>
    <description>Subjects will be required to complete the 19 questions - LCQ, which is a symptom specific questionnaire designed to assess the impact of cough severity, a major symptom of IPF. Subjects will be required to complete the 19 questions of the LCQ on Day 1 and the Final Dosing Day</description>
  </secondary_outcome>
  <number_of_arms>12</number_of_arms>
  <enrollment type="Actual">17</enrollment>
  <condition>Idiopathic Pulmonary Fibrosis</condition>
  <arm_group>
    <arm_group_label>Cohort 1-GSK2126458</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will be randomized in 3:1 ratio to receive either GSK2126458 (0.25 mg twice daily [bid]) or placebo for approximately 8 days (7 to 10 days dosing)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 1-Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Subjects will be randomized in 3:1 ratio to receive either GSK2126458 bid or matching placebo for approximately 8 days (7 to 10 days dosing)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 2-GSK2126458</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will be randomized in 3:1 ratio to receive either GSK2126458 bid or placebo for approximately 8 days (7 to 10 days dosing). GSK2126458 dose will be decided from Cohort 1 and which could be escalated or deescalated or repeated from Cohort 1 dosing.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 2-Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Subjects will be randomized in 3:1 ratio to receive either GSK2126458 bid or matching placebo for approximately 8 days (7 to 10 days dosing).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 3- GSK2126458</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will be randomized in 3:1 ratio to receive either GSK2126458 bid or placebo for approximately 8 days (7 to 10 days dosing). GSK2126458 dose will be decided from Cohort 2 and which could be escalated or deescalated or repeated from Cohort 2 dosing.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 3-Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Subjects will be randomized in 3:1 ratio to receive either GSK2126458 bid or matching placebo for approximately 8 days (7 to 10 days dosing).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 4- GSK2126458</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will be randomized in 3:1 ratio to receive either GSK2126458 bid or placebo for approximately 8 days (7 to 10 days dosing). GSK2126458 dose will be decided from Cohort 3 and which could be escalated or deescalated or repeated from Cohort 3 dosing.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 4- Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Subjects will be randomized in 3:1 ratio to receive either GSK2126458 bid or matching placebo for approximately 8 days (7 to 10 days dosing).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 5- GSK2126458</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will be randomized in 3:1 ratio to receive either GSK2126458 bid or placebo for approximately 8 days (7 to 10 days dosing). GSK2126458 dose will be decided from Cohort 4 and which could be escalated or deescalated or repeated from Cohort 4 dosing.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 5- Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Subjects will be randomized in 3:1 ratio to receive either GSK2126458 bid or matching placebo for approximately 8 days (7 to 10 days dosing).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 6- GSK2126458</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will be randomized in 3:1 ratio to receive either GSK2126458 bid or placebo for approximately 8 days (7 to 10 days dosing). GSK2126458 dose will be decided from Cohort 4 and which could be escalated or deescalated or repeated from Cohort 5 dosing.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cohort 6- Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Subjects will be randomized in 3:1 ratio to receive either GSK2126458 bid or matching placebo for approximately 8 days (7 to 10 days dosing).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>GSK2126458</intervention_name>
    <description>GSK2126458 will be available as film coated tablet of dose strength 0.25 mg and 0.5 mg</description>
    <arm_group_label>Cohort 1-GSK2126458</arm_group_label>
    <arm_group_label>Cohort 2-GSK2126458</arm_group_label>
    <arm_group_label>Cohort 3- GSK2126458</arm_group_label>
    <arm_group_label>Cohort 4- GSK2126458</arm_group_label>
    <arm_group_label>Cohort 5- GSK2126458</arm_group_label>
    <arm_group_label>Cohort 6- GSK2126458</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Matching placebo will be available</description>
    <arm_group_label>Cohort 1-Placebo</arm_group_label>
    <arm_group_label>Cohort 2-Placebo</arm_group_label>
    <arm_group_label>Cohort 3-Placebo</arm_group_label>
    <arm_group_label>Cohort 4- Placebo</arm_group_label>
    <arm_group_label>Cohort 5- Placebo</arm_group_label>
    <arm_group_label>Cohort 6- Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diagnosis of IPF as determined by a responsible and experienced chest physician and&#xD;
             based on established criteria defined by the American Thoracic Society/European&#xD;
             Respiratory Society: American Thoracic Society/European Respiratory Society&#xD;
             International Multidisciplinary Consensus Classification of the Idiopathic&#xD;
             Interstitial Pneumonias.&#xD;
&#xD;
          -  FVC greater than (&gt;) 40% predicted and Diffusing capacity of the Lung for Carbon&#xD;
             Monoxide (DLCO) &gt;30% predicted&#xD;
&#xD;
          -  Alanine aminotransferase (ALT) less than (&lt;) 2x upper limit of normal (ULN); alkaline&#xD;
             phosphatase and bilirubin less than or equal to (&lt;=) 1.5xULN.&#xD;
&#xD;
          -  QTcB &lt;450 milliseconds (msec) and QTc interval &lt;=480 msec; or QTc &lt;480 msec in&#xD;
             subjects with Bundle Branch Block.&#xD;
&#xD;
          -  Male over 45 years of age inclusive, or female over 50 years of age inclusive at the&#xD;
             time of signing the informed consent&#xD;
&#xD;
          -  A female subject is eligible to participate if she is of non-childbearing potential&#xD;
             defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or&#xD;
             postmenopausal defined as 12 months of spontaneous amenorrhoea. Females on hormone&#xD;
             replacement therapy (HRT) and whose menopausal status is in doubt will be required to&#xD;
             use one of the contraception, if they wish to continue their HRT during the study.&#xD;
             Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status&#xD;
             prior to study enrolment. For most forms of HRT, at least 2 to 4 weeks should elapse&#xD;
             between the cessation of therapy and the blood draw; this interval depends on the type&#xD;
             and dosage of HRT. Following confirmation of their post-menopausal status, they can&#xD;
             resume use of HRT during the study without use of a contraceptive method.&#xD;
&#xD;
          -  Male subjects with female partners of child-bearing potential must agree to use one of&#xD;
             the contraception methods. This criterion must be followed from the time of the first&#xD;
             dose of study medication until the follow-up contact.&#xD;
&#xD;
          -  Body weight &gt;=40 kilogram (kg) (female), &gt;=50 kg (male), and body mass index (BMI)&#xD;
             between 20 and 35 kg/meter squared (m^2) inclusive.&#xD;
&#xD;
          -  Subjects must have left ventricular ejection fraction (LVEF) &gt;=50 % as demonstrated by&#xD;
             a recent echocardiogram (at screening or within 3 months prior to screening).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Current IPF exacerbation&#xD;
&#xD;
          -  History of acute coronary syndromes, atrial fibrillation, coronary angioplasty, or&#xD;
             stenting within the past 24 weeks.&#xD;
&#xD;
          -  Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA)&#xD;
             functional classification system&#xD;
&#xD;
          -  Uncontrolled hypertension or a history of conditions which could increase the risk of&#xD;
             complications from hypertension&#xD;
&#xD;
          -  Current upper or lower respiratory tract infection&#xD;
&#xD;
          -  Repeated systolic BP &gt;=160 millimeters of mercury (mmHg) and/or diastolic BP &gt;=90 mmHg&#xD;
             unless they are diabetic, in which case subjects with repeated systolic BP &gt;=145 mmHg&#xD;
             and/or diastolic &gt;=85 mmHg&#xD;
&#xD;
          -  Poorly controlled diabetes (HbA1c [glycated hemoglobin (hemoglobin A1c)] &gt;7.5%).&#xD;
&#xD;
          -  Clinically significant laboratory assessment outside the reference range unless the&#xD;
             Investigator considers that the finding is unlikely to introduce additional risk&#xD;
             factors and will not interfere with the study procedures&#xD;
&#xD;
          -  A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody&#xD;
             result within 3 months of screening&#xD;
&#xD;
          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities&#xD;
&#xD;
          -  Previous exposure to ionising radiation &gt;5 millisievert (mSv) in the 3 years prior to&#xD;
             enrolment&#xD;
&#xD;
          -  History of regular alcohol consumption within 6 months of the study defined as: an&#xD;
             average weekly intake of &gt;21 units for males or &gt;14 units for females. One unit is&#xD;
             equivalent to 8 g of alcohol: a half-pint (approximately 240 milliliters [mL]) of&#xD;
             beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits&#xD;
&#xD;
          -  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: 30 days, 5 half-lives or twice the duration of the biological effect of the&#xD;
             investigational product (whichever is longer).&#xD;
&#xD;
          -  Exposure to more than four new chemical entities within 12 months prior to the first&#xD;
             dosing day&#xD;
&#xD;
          -  Currently taking Pirfenidone or have received Pirfenidone within the previous 30 days&#xD;
&#xD;
          -  Unable to refrain from the use of prohibited prescription or non-prescription drugs,&#xD;
             unless in the opinion of the Investigator and GSK Medical Monitor the medication will&#xD;
             not interfere with the study procedures or compromise subject safety&#xD;
&#xD;
          -  History of sensitivity to any of the study medications, or components there of 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;
          -  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;
          -  History of sensitivity to heparin or heparin-induced thrombocytopenia&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>45 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</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>SW3 6NP</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <reference>
    <citation>Lukey PT, Harrison SA, Yang S, Man Y, Holman BF, Rashidnasab A, Azzopardi G, Grayer M, Simpson JK, Bareille P, Paul L, Woodcock HV, Toshner R, Saunders P, Molyneaux PL, Thielemans K, Wilson FJ, Mercer PF, Chambers RC, Groves AM, Fahy WA, Marshall RP, Maher TM. A randomised, placebo-controlled study of omipalisib (PI3K/mTOR) in idiopathic pulmonary fibrosis. Eur Respir J. 2019 Mar 18;53(3):1801992. doi: 10.1183/13993003.01992-2018. Print 2019 Mar.</citation>
    <PMID>30765508</PMID>
  </reference>
  <verification_date>November 2019</verification_date>
  <study_first_submitted>November 8, 2012</study_first_submitted>
  <study_first_submitted_qc>November 8, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 12, 2012</study_first_posted>
  <last_update_submitted>November 19, 2019</last_update_submitted>
  <last_update_submitted_qc>November 19, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">November 21, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Pulmonary Fibrosis</mesh_term>
    <mesh_term>Idiopathic Pulmonary Fibrosis</mesh_term>
    <mesh_term>Fibrosis</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>IPD for this study will be made available via the Clinical Study Data Request site.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>IPD is available via the Clinical Study Data Request site (click on the link provided below)</ipd_time_frame>
    <ipd_access_criteria>Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.</ipd_access_criteria>
    <ipd_url>https://clinicalstudydatarequest.com/Posting.aspx?ID=20056</ipd_url>
  </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/NCT01725139
org study id: 116711
secondary id: 2012-001376-11
nct id: NCT01725139
lead sponsor: 
has dmc: No
This is a dose escalation/dose finding, double-blind, placebo-controlled, parallel study of
      GSK2126458 in subjects with IPF. The study is designed to explore a number of doses of
      GSK2126458 for engagement of pharmacology after short term dosing. It is anticipated that
      approximately 24 subjects will be enrolled in this study. Actual number of cohorts in this
      study could vary up to a maximum of 6 cohorts (n=4/cohort; 3 on active and 1 on placebo).

      Each cohort will consist of four subjects who will be randomised to receive GSK2126458 (three
      subjects) or placebo (one subject) for approximately 8 days (7 to 10 days). On Day 1 they
      will receive their first dose of GSK2126458 (or placebo) and safety, tolerability and PK/PD
      in the blood will be measured for up to 8 hours post-dose. Subjects will then be discharged
      from the site with study drug until the last day of dosing. They will also receive hand held
      spirometers and instructions on action to be taken in case of deterioration in pulmonary
      function or any other adverse events (AEs). On the last day of dosing they will return to the
      site for a repeat of the Day 1 procedures.

      A bronchoalveolar lavage (BAL) and [18F]-fluoro-deoxyglucose (FDG)- positron emission
      tomography / computed tomography (PET/CT) scan will be conducted twice during the study;
      once, at least 2 days before dosing commences and again during the course of the dosing
      period.

      After the final subject in each cohort has completed dosing, a dose escalation meeting will
      take place. Safety and tolerability and PK data will be reviewed during this meeting and
      decisions made may include but are not limited to: escalate the dose, decrease the dose or
      repeat the same dose in the next cohort; stop the study.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Pharmacodynamic (PD) endpoints pAKT/AKT in platelet-rich plasma and BAL cells, [18F]-FDG-PET/CT
time frame: Baseline, Day 1, mid-study BAL visit (Day 5-9) and final dosing day (Day 7, 8, 9 or 10) for each cohort
description: Pharmacodynamic will be measured by inhibition of pAKT/AKT in platelet-rich plasma and BAL cells, as well as inhibition of glucose uptake as measured by thoracic[18F]-FDG-PET/CT
measure: Area under the curve (AUC) in blood for GSK2126458
time frame: Day 1, mid-study PET visit (Day 4-8), mid-study BAL visit (Day 5-9) and final dosing day post-dose (Day 7, 8, 9 or 10) for each cohort
description: GSK2126458 PK parameters in blood in order to define the blood and pulmonary PK/PD relationship for GSK2126458 in IPF subjects
measure: Maximum observed concentration (Cmax) in blood for GSK2126458
time frame: Day 1, mid-study PET visit (Day 4-8), mid-study BAL visit (Day 5-9) and final dosing day post-dose (Day 7, 8, 9 or 10) for each cohort
description: GSK2126458 PK parameters in blood in order to define the blood and pulmonary PK/PD relationship for GSK2126458 in IPF subjects
measure: Pre-dose (trough) concentration at the end of the dosing interval (Ctrough) in blood for GSK2126458
time frame: Day 1, mid-study PET visit (Day 4-8), mid-study BAL visit (Day 5-9) and final dosing day post-dose (Day 7, 8, 9 or 10) for each cohort
description: GSK2126458 PK parameters in blood in order to define the blood and pulmonary PK/PD relationship for GSK2126458 in IPF subjects
measure: Concentration of GSK2126458 in bronchoalveolar lavage fluid (BALF)
time frame: Baseline BAL visit and mid-study BAL visit (Day 5-9).
description: GSK2126458 concentration in BALF in order to define the pulmonary PK/PD relationship for GSK2126458 in IPF subjects
measure: Safety and tolerability of GSK2126458 as assessed by number of subjects with adverse events (AE)s
time frame: Baseline up to final dosing day (Day 7, 8, 9 or 10) for each cohort
description: Safety and tolerability parameters will include recording of AEs, throughout the study in subjects with IPF
measure: Safety and tolerability of GSK2126458 as assessed by change from baseline in vital signs
time frame: Day 1, final dosing day (Day 7, 8, 9 or 10) and follow-up (10-14 days post last dose), for each cohort
description: Vital sign measurement will be done in a semi-supine position and will include systolic and diastolic blood pressure, pulse rate and tympanic temperature
measure: Safety and tolerability of GSK2126458 as assessed by change from baseline in clinical laboratory parameters
time frame: Day 1, mid-study BAL visit (Day 5-9), final dosing day (Day 7, 8, 9 or 10) and follow-up (10-14 days post last dose) for each cohort
description: Clinical laboratory assessments will include haematology, clinical chemistry, urinalysis and additional parameters
measure: Safety and tolerability of GSK2126458 as assessed by change from baseline in pulmonary function
time frame: Recorded daily from screening until final dosing day (Day 7, 8, 9 or 10) for each cohort
description: Pulmonary function will be assessed by spirometry to test the forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)
measure: Safety and tolerability of GSK2126458 as assessed by change from baseline in electrocardiogram (ECG)
time frame: Screening, Day 1 and final dosing day (Day 7, 8, 9 or 10) for each study cohort
description: Single 12-lead ECG will be obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT and QTc intervals
measure: Assessment of subject's breathlessness using MRC dyspnoea scale
time frame: Day 1 and final dosing day (Day 7, 8, 9 or 10) for each study cohort
description: The Medical Research Council (MRC) dyspnoea scale is a 5-point scale used for grading the degree of a patient's breathlessness.
measure: Assessment of FEV1 and FVC using daily hand-held spirometry
time frame: Recorded daily from screening until final dosing day (Day 7, 8, 9 or 10) for each cohort
description: Subjects will be required to record their daily spirometry scores (FEV1 and FVC) using hand-held spirometers, at approximately the same time each morning between Screening and the Final Dosing Day
measure: Investigate the effect of GSK2126458 on the frequency and or severity of chronic cough using Leicester Cough Questionnaire (LCQ) in IPF subjects
time frame: Day 1 and final dosing day (Day 7, 8, 9 or 10) for each cohort
description: Subjects will be required to complete the 19 questions - LCQ, which is a symptom specific questionnaire designed to assess the impact of cough severity, a major symptom of IPF. Subjects will be required to complete the 19 questions of the LCQ on Day 1 and the Final Dosing Day
arm group label: Cohort 1-GSK2126458
arm group type: Experimental
description: Subjects will be randomized in 3:1 ratio to receive either GSK2126458 (0.25 mg twice daily [bid]) or placebo for approximately 8 days (7 to 10 days dosing)
arm group label: Cohort 1-Placebo
arm group type: Placebo Comparator
description: Subjects will be randomized in 3:1 ratio to receive either GSK2126458 bid or matching placebo for approximately 8 days (7 to 10 days dosing)
arm group label: Cohort 2-GSK2126458
arm group type: Experimental
description: Subjects will be randomized in 3:1 ratio to receive either GSK2126458 bid or placebo for approximately 8 days (7 to 10 days dosing). GSK2126458 dose will be decided from Cohort 1 and which could be escalated or deescalated or repeated from Cohort 1 dosing.
arm group label: Cohort 2-Placebo
arm group type: Placebo Comparator
description: Subjects will be randomized in 3:1 ratio to receive either GSK2126458 bid or matching placebo for approximately 8 days (7 to 10 days dosing).
arm group label: Cohort 3- GSK2126458
arm group type: Experimental
description: Subjects will be randomized in 3:1 ratio to receive either GSK2126458 bid or placebo for approximately 8 days (7 to 10 days dosing). GSK2126458 dose will be decided from Cohort 2 and which could be escalated or deescalated or repeated from Cohort 2 dosing.
arm group label: Cohort 3-Placebo
arm group type: Placebo Comparator
description: Subjects will be randomized in 3:1 ratio to receive either GSK2126458 bid or matching placebo for approximately 8 days (7 to 10 days dosing).
arm group label: Cohort 4- GSK2126458
arm group type: Experimental
description: Subjects will be randomized in 3:1 ratio to receive either GSK2126458 bid or placebo for approximately 8 days (7 to 10 days dosing). GSK2126458 dose will be decided from Cohort 3 and which could be escalated or deescalated or repeated from Cohort 3 dosing.
arm group label: Cohort 4- Placebo
arm group type: Placebo Comparator
description: Subjects will be randomized in 3:1 ratio to receive either GSK2126458 bid or matching placebo for approximately 8 days (7 to 10 days dosing).
arm group label: Cohort 5- GSK2126458
arm group type: Experimental
description: Subjects will be randomized in 3:1 ratio to receive either GSK2126458 bid or placebo for approximately 8 days (7 to 10 days dosing). GSK2126458 dose will be decided from Cohort 4 and which could be escalated or deescalated or repeated from Cohort 4 dosing.
arm group label: Cohort 5- Placebo
arm group type: Placebo Comparator
description: Subjects will be randomized in 3:1 ratio to receive either GSK2126458 bid or matching placebo for approximately 8 days (7 to 10 days dosing).
arm group label: Cohort 6- GSK2126458
arm group type: Experimental
description: Subjects will be randomized in 3:1 ratio to receive either GSK2126458 bid or placebo for approximately 8 days (7 to 10 days dosing). GSK2126458 dose will be decided from Cohort 4 and which could be escalated or deescalated or repeated from Cohort 5 dosing.
arm group label: Cohort 6- Placebo
arm group type: Placebo Comparator
description: Subjects will be randomized in 3:1 ratio to receive either GSK2126458 bid or matching placebo for approximately 8 days (7 to 10 days dosing).
intervention type: Drug
intervention name: GSK2126458
description: GSK2126458 will be available as film coated tablet of dose strength 0.25 mg and 0.5 mg
arm group label: Cohort 1-GSK2126458
arm group label: Cohort 2-GSK2126458
arm group label: Cohort 3- GSK2126458
arm group label: Cohort 4- GSK2126458
arm group label: Cohort 5- GSK2126458
arm group label: Cohort 6- GSK2126458
intervention type: Drug
intervention name: Placebo
description: Matching placebo will be available
arm group label: Cohort 1-Placebo
arm group label: Cohort 2-Placebo
arm group label: Cohort 3-Placebo
arm group label: Cohort 4- Placebo
arm group label: Cohort 5- Placebo
arm group label: Cohort 6- Placebo
criteria: 
gender: All
minimum age: 45 Years
maximum age: N/A
healthy volunteers: No
last name: GSK Clinical Trials
role: Study Director
affiliation: GlaxoSmithKline
facility: 
country: United Kingdom
citation: Lukey PT, Harrison SA, Yang S, Man Y, Holman BF, Rashidnasab A, Azzopardi G, Grayer M, Simpson JK, Bareille P, Paul L, Woodcock HV, Toshner R, Saunders P, Molyneaux PL, Thielemans K, Wilson FJ, Mercer PF, Chambers RC, Groves AM, Fahy WA, Marshall RP, Maher TM. A randomised, placebo-controlled study of omipalisib (PI3K/mTOR) in idiopathic pulmonary fibrosis. Eur Respir J. 2019 Mar 18;53(3):1801992. doi: 10.1183/13993003.01992-2018. Print 2019 Mar.
PMID: 30765508
responsible party type: Sponsor
mesh term: Pulmonary Fibrosis
mesh term: Idiopathic Pulmonary Fibrosis
mesh term: Fibrosis
sharing ipd: Yes
ipd description: IPD for this study will be made available via the Clinical Study Data Request site.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd time frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
ipd access criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
ipd url: https://clinicalstudydatarequest.com/Posting.aspx?ID=20056