A Proof of Mechanism Study With GSK2126458 in Patients With Idiopathic Pulmonary Fibrosis (IPF)

This study is currently recruiting participants. (see Contacts and Locations)
Verified November 2013 by GlaxoSmithKline
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01725139
First received: November 8, 2012
Last updated: July 24, 2014
Last verified: November 2013
  Purpose

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.


Condition Intervention Phase
Idiopathic Pulmonary Fibrosis
Drug: GSK2126458
Drug: Placebo
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Randomised, Placebo-controlled, Double-blind, Repeat Dose Escalation Study With GSK2126458 in Patients With Idiopathic Pulmonary Fibrosis (IPF)

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    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

  • 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 ] [ Designated as safety issue: No ]
    GSK2126458 PK parameters in blood in order to define the blood and pulmonary PK/PD relationship for GSK2126458 in IPF subjects

  • 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 ] [ Designated as safety issue: No ]
    GSK2126458 PK parameters in blood in order to define the blood and pulmonary PK/PD relationship for GSK2126458 in IPF subjects

  • 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 ] [ Designated as safety issue: No ]
    GSK2126458 PK parameters in blood in order to define the blood and pulmonary PK/PD relationship for GSK2126458 in IPF subjects

  • Concentration of GSK2126458 in bronchoalveolar lavage fluid (BALF) [ Time Frame: Baseline BAL visit and mid-study BAL visit (Day 5-9). ] [ Designated as safety issue: No ]
    GSK2126458 concentration in BALF in order to define the pulmonary PK/PD relationship for GSK2126458 in IPF subjects


Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]
    Safety and tolerability parameters will include recording of AEs, throughout the study in subjects with IPF

  • 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 ] [ Designated as safety issue: No ]
    Vital sign measurement will be done in a semi-supine position and will include systolic and diastolic blood pressure, pulse rate and tympanic temperature

  • 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 ] [ Designated as safety issue: No ]
    Clinical laboratory assessments will include haematology, clinical chemistry, urinalysis and additional parameters

  • 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 ] [ Designated as safety issue: No ]
    Pulmonary function will be assessed by spirometry to test the forced expiratory volume in one second (FEV1) and forced vital capacity (FVC)

  • 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 ] [ Designated as safety issue: No ]
    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

  • 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 ] [ Designated as safety issue: No ]
    The Medical Research Council (MRC) dyspnoea scale is a 5-point scale used for grading the degree of a patient's breathlessness.

  • 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 ] [ Designated as safety issue: No ]
    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

  • 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 ] [ Designated as safety issue: No ]
    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


Estimated Enrollment: 30
Study Start Date: March 2013
Estimated Study Completion Date: July 2014
Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1-GSK2126458
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)
Drug: GSK2126458
GSK2126458 will be available as film coated tablet of dose strength 0.25 mg and 0.5 mg
Placebo Comparator: Cohort 1-Placebo
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)
Drug: Placebo
Matching placebo will be available
Experimental: Cohort 2-GSK2126458
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.
Drug: GSK2126458
GSK2126458 will be available as film coated tablet of dose strength 0.25 mg and 0.5 mg
Placebo Comparator: Cohort 2-Placebo
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).
Drug: Placebo
Matching placebo will be available
Experimental: Cohort 3- GSK2126458
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.
Drug: GSK2126458
GSK2126458 will be available as film coated tablet of dose strength 0.25 mg and 0.5 mg
Placebo Comparator: Cohort 3-Placebo
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).
Drug: Placebo
Matching placebo will be available
Experimental: Cohort 4- GSK2126458
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.
Drug: GSK2126458
GSK2126458 will be available as film coated tablet of dose strength 0.25 mg and 0.5 mg
Placebo Comparator: Cohort 4- Placebo
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).
Drug: Placebo
Matching placebo will be available
Experimental: Cohort 5- GSK2126458
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.
Drug: GSK2126458
GSK2126458 will be available as film coated tablet of dose strength 0.25 mg and 0.5 mg
Placebo Comparator: Cohort 5- Placebo
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).
Drug: Placebo
Matching placebo will be available
Experimental: Cohort 6- GSK2126458
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.
Drug: GSK2126458
GSK2126458 will be available as film coated tablet of dose strength 0.25 mg and 0.5 mg
Placebo Comparator: Cohort 6- Placebo
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).
Drug: Placebo
Matching placebo will be available

  Eligibility

Ages Eligible for Study:   45 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of IPF as determined by a responsible and experienced chest physician and based on established criteria defined by the American Thoracic Society/European Respiratory Society: American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias.
  • FVC greater than (>) 40% predicted and Diffusing capacity of the Lung for Carbon Monoxide (DLCO) >30% predicted
  • Alanine aminotransferase (ALT) less than (<) 2x upper limit of normal (ULN); alkaline phosphatase and bilirubin less than or equal to (<=) 1.5xULN.
  • QTcB <450 milliseconds (msec) and QTc interval <=480 msec; or QTc <480 msec in subjects with Bundle Branch Block.
  • Male over 45 years of age inclusive, or female over 50 years of age inclusive at the time of signing the informed consent
  • A female subject is eligible to participate if she is of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhoea. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception, if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrolment. For most forms of HRT, at least 2 to 4 weeks should elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.
  • Male subjects with female partners of child-bearing potential must agree to use one of the contraception methods. This criterion must be followed from the time of the first dose of study medication until the follow-up contact.
  • Body weight >=40 kilogram (kg) (female), >=50 kg (male), and body mass index (BMI) between 20 and 35 kg/meter squared (m^2) inclusive.
  • Subjects must have left ventricular ejection fraction (LVEF) >=50 % as demonstrated by a recent echocardiogram (at screening or within 3 months prior to screening).

Exclusion Criteria:

  • Current IPF exacerbation
  • History of acute coronary syndromes, atrial fibrillation, coronary angioplasty, or stenting within the past 24 weeks.
  • Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system
  • Uncontrolled hypertension or a history of conditions which could increase the risk of complications from hypertension
  • Current upper or lower respiratory tract infection
  • Repeated systolic BP >=160 millimeters of mercury (mmHg) and/or diastolic BP >=90 mmHg unless they are diabetic, in which case subjects with repeated systolic BP >=145 mmHg and/or diastolic >=85 mmHg
  • Poorly controlled diabetes (HbA1c [glycated hemoglobin (hemoglobin A1c)] >7.5%).
  • Clinically significant laboratory assessment outside the reference range unless the Investigator considers that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures
  • A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities
  • Previous exposure to ionising radiation >5 millisievert (mSv) in the 3 years prior to enrolment
  • History of regular alcohol consumption within 6 months of the study defined as: an average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (approximately 240 milliliters [mL]) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits
  • Subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
  • Exposure to more than four new chemical entities within 12 months prior to the first dosing day
  • Currently taking Pirfenidone or have received Pirfenidone within the previous 30 days
  • Unable to refrain from the use of prohibited prescription or non-prescription drugs, unless in the opinion of the Investigator and GSK Medical Monitor the medication will not interfere with the study procedures or compromise subject safety
  • History of sensitivity to any of the study medications, or components there of or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation
  • Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period
  • History of sensitivity to heparin or heparin-induced thrombocytopenia
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01725139

Contacts
Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com

Locations
United Kingdom
GSK Investigational Site Recruiting
London, United Kingdom, SW3 6NP
Contact: US GSK Clinical Trials Call Center    877-379-3718    GSKClinicalSupportHD@gsk.com   
Contact: EU GSK Clinical Trials Call Center    +44 (0) 20 8990 4466    GSKClinicalSupportHD@gsk.com   
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01725139     History of Changes
Other Study ID Numbers: 116711
Study First Received: November 8, 2012
Last Updated: July 24, 2014
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Additional relevant MeSH terms:
Fibrosis
Pulmonary Fibrosis
Idiopathic Pulmonary Fibrosis
Pathologic Processes
Lung Diseases
Respiratory Tract Diseases
Idiopathic Interstitial Pneumonias
Lung Diseases, Interstitial

ClinicalTrials.gov processed this record on July 26, 2014