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A Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Single and Repeat Doses of the Dry Powder Formulation of GSK2269557 in Healthy Subjects

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01762878
First Posted: January 8, 2013
Last Update Posted: July 13, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
GlaxoSmithKline
  Purpose

GSK2269557 is potent and highly selective inhaled phosphoinositides 3-kinases -delta (PI3K-delta) inhibitor being developed as an anti-inflammatory agent for the treatment of inflammatory airway diseases. GSK2269557 has already been administered as a nebulized solution in single and repeat doses to humans and has been well tolerated across the range of doses used. The purpose of this study is to evaluate the safety, tolerability and pharmacokinetics of single and repeat inhaled doses of GSK2269557 as a dry powder. This study is the first administration of dry powder GSK2269557 in humans.

Part A will consist of four treatment periods separated by at least 14 days wash out periods. In each treatment period there will be 12 subjects receiving GSK2269557 and 4 subjects receiving placebo. The doses of GSK2269557 planned for Part A are 100 micrograms (mcg), 500 mcg and 3000 mcg. Blinded safety and available pharmacokinetic (PK) data will be reviewed before each dose escalation. Part B will be a parallel group design conducted in a separate group of subjects from Part A. Nine subjects will receive repeat doses of GSK2269557 and 3 subjects will receive repeat doses of placebo for 14 days. The total daily dose will be the same as the dose that was well tolerated in Part A. The study duration, including screening and follow-up, is not expected to exceed 82 days for subjects in part A and 55 days for subjects in part B of the study.


Condition Intervention Phase
Pulmonary Disease, Chronic Obstructive Drug: GSK2269557 Drug: Placebo Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Single-Centre, Double-Blind, Placebo Controlled Two Part Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Single and Repeat Doses of GSK2269557 as a Dry Powder in Healthy Subjects Who Smoke Cigarettes

Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Safety and tolerability of single ascending doses assessed by clinical monitoring of blood pressure [ Time Frame: up to 52 days ]
    Blood pressure measurement will include systolic and diastolic blood pressure measured after resting in the supine position for 5 minutes

  • Safety and tolerability of repeat doses assessed by clinical monitoring of blood pressure [ Time Frame: up to 24 days ]
    Pulse rate measurement should be done after resting in the supine position for 5 minutes

  • Safety and tolerability of single ascending doses assessed by pulse rate [ Time Frame: up to 52 days ]
    Pulse rate measurement should be done after resting in the supine position for 5 minutes

  • Safety and tolerability of repeat doses assessed by pulse rate [ Time Frame: up to 24 days ]
    Pulse rate measurement should be done after resting in the supine position for 5 minutes

  • Safety and tolerability of single ascending doses assessed by spirometry (FEV1) [ Time Frame: up to 52 days ]
    Pulmonary function test measured from forced expiratory volume in 1 second (FEV1). Pulmonary function test will be repeated until three technically acceptable measurements have been made.

  • Safety and tolerability of repeat doses assessed by spirometry [ Time Frame: up to 24 days ]
    Pulmonary function test measured from FEV1. Pulmonary function test will be repeated until three technically acceptable measurements have been made.

  • Safety and tolerability of single ascending doses assessed by Electrocardiogram (ECG) [ Time Frame: up to 52 days ]
    12-lead ECGs will be obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QT duration corrected for heart rate by Bazett's formula (QTcB)/ QT duration corrected for heart rate by Fridericia's formula (QTcF) intervals. ECGs will be measured after resting in supine position for 5 minutes

  • Safety and tolerability of repeat doses assessed by ECG [ Time Frame: up to 24 days ]
    12-lead ECGs will be obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTcB/QTcF intervals. ECGs will be measured after resting in supine position for 5 minutes

  • Safety and tolerability of single ascending doses assessed by clinical laboratory test [ Time Frame: up to 52 days ]
    Clinical laboratory test includes hematology, clinical chemistry, urinalysis and additional parameters

  • Safety and tolerability of repeat doses assessed by clinical laboratory test [ Time Frame: up to 24 days ]
    Clinical laboratory test includes hematology, clinical chemistry, urinalysis and additional parameters

  • Safety and tolerability of single ascending doses assessed by number of subjects with adverse events (AEs) [ Time Frame: up to 52 days ]
    AEs will be collected from the start of study treatment and until the follow-up contact

  • Safety and tolerability of repeat doses assessed by number of subjects with AEs [ Time Frame: up to 24 days ]
    AEs will be collected from the start of study treatment and until the follow-up contact


Secondary Outcome Measures:
  • Single ascending doses plasma GSK2269557 PK assessed by AUC (0-t) and AUC (0-infinity) [ Time Frame: 2 days of each treatment period in part A. Blood samples (2 mililiter [mL]) for plasma PK parameters will be collected on Day 1(pre-dose, 0.083, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12 hrs post dose) and on Day 2 (24 hrs post dose). ]
    To evaluate the single ascending doses PK, area under the time-concentration curve from time zero (pre-dose) to last time of quantifiable concentration (AUC[0-t]) and AUC from zero to infinity (AUC[0-infinity]) following single ascending doses will be assessed

  • Repeat doses plasma GSK2269557 PK assessed by AUC (0-t) and AUC (0-infinity) [ Time Frame: 15 days of part B. Blood samples (2 mL) for plasma PK parameters will be collected on Day 1 through Day 13 (pre-dose and 0.083 hrs post dose), on Day 14 (pre-dose, 0.083, 0.5, 0.75, 1, 2, 3, 4, 6, 8, and 12 hrs post dose), and on Day 15 (24 hrs post dose ]
    To evaluate the repeat doses PK, (AUC[0-t]) and (AUC[0-infinity]) following repeated doses will be assessed

  • Single ascending doses plasma GSK2269557 PK assessed by Cmax and Ctau [ Time Frame: 2 days of each treatment period in part A. Blood samples (2 mL) for plasma PK parameters will be collected on Day 1(pre-dose, 0.083, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12 hrs post dose) and on Day 2 (24 hrs post dose). ]
    To evaluate the single ascending doses PK, maximum observed concentration (Cmax) and pre-dose (trough) concentration at the end of the dosing interval (Ctau) following single ascending doses will be assessed.

  • Repeat doses plasma GSK2269557 PK assessed by Cmax and Ctau [ Time Frame: 15 days of part B. Blood samples (2 mL) for plasma PK parameters will be collected on Day 1 through Day 13 (pre-dose and 0.083 hrs post dose), on Day 14 (pre-dose, 0.083, 0.5, 0.75, 1, 2, 3, 4, 6, 8, and 12 hrs post dose), and on Day 15 (24 hrs post dose ]
    To evaluate the repeat doses PK, Cmax and Ctau following repeated doses will be assessed

  • Single ascending doses plasma GSK2269557 PK assessed by Tmax and T1/2 [ Time Frame: 2 days of each treatment period in part A. Blood samples (2 mL) for plasma PK parameters will be collected on Day 1(pre-dose, 0.083, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12 hrs post dose) and on Day 2 (24 hrs post dose). ]
    To evaluate the single ascending doses PK, time to occurrence of Cmax and terminal phase half-life (T1/2) following single ascending doses will be assessed.

  • Repeat doses plasma GSK2269557 PK assessed by Tmax and T1/2 [ Time Frame: 15 days of part B. Blood samples (2 mL) for plasma PK parameters will be collected on Day 1 through Day 13 (pre-dose and 0.083 hrs post dose), on Day 14 (pre-dose, 0.083, 0.5, 0.75, 1, 2, 3, 4, 6, 8, and 12 hrs post dose), and on Day 15 (24 hrs post dose ]
    To evaluate the repeat doses PK, Tmax and T1/2 following repeated doses will be assessed.

  • Steady state concentration assessed by BAL concentrations of GSK2269557 and derived ELF and cell pellet deposition after repeat doses [ Time Frame: Day 15 of Part B ]
    To investigate the steady-state trough concentration of GSK2269557 in lung after repeat doses, bronchial alveolar lavage (BAL) samples collected during bronchoscopy and derived epithelial lining fluid (ELF) and BAL cell pellet will be analyzed.

  • BAL and plasma concentrations of urea [ Time Frame: Day 15 of Part B ]
    To investigate the steady-state trough concentration of GSK2269557 after repeat doses.

  • Single ascending doses PD effect of GSK2269557 assessed by PIP3 in sputum cells [ Time Frame: Up to 52 days ]
    Sputum samples will be collected to evaluate single ascending doses pharmacodynamic (PD) effect of GSK2269557 on biomarker Phosphatidylinositol (3,4,5)-trisphosphate (PIP3) peak area as a proportion of (PIP3 peak area + PIP2 peak area) in sputum cells

  • Repeat doses PD effect of GSK2269557 assessed by PIP3 in sputum cells [ Time Frame: Up to 14 days (Part B) ]
    Sputum samples will be collected to evaluate repeat doses PD effect of GSK2269557 on biomarker PIP3 peak area as a proportion of (PIP3 peak area + PIP2 peak area) in sputum cells


Enrollment: 45
Actual Study Start Date: January 9, 2013
Study Completion Date: October 21, 2013
Primary Completion Date: October 21, 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: GSK2269557 100 mcg arm
Each subject will receive 4 treatments in 4 treatment periods in Part A of the study. Subjects in this arm will be randomized to receive GSK2269557 100 mcg in one of the 4 treatment periods.
Drug: GSK2269557
Dry powder for oral inhalation (100 and 500 mcg /blister) once daily using DIKUS device. The doses of GSK2269557 planned for Part A are: 100 mcg, 500 mcg and 3000 mcg
Experimental: GSK2269557 500 mcg arm
Each subject will undergo 4 treatments in 4 treatment periods in Part A of the study. Subjects in this arm will be randomized to receive GSK2269557 500 mcg in one of the 4 treatment periods
Drug: GSK2269557
Dry powder for oral inhalation (100 and 500 mcg /blister) once daily using DIKUS device. The doses of GSK2269557 planned for Part A are: 100 mcg, 500 mcg and 3000 mcg
Experimental: GSK2269557 3000 mcg arm
Each subject will undergo 4 treatments in 4 treatment periods in Part A of the study. Subjects in this arm will be randomized to receive GSK2269557 3000 mcg in one of the 4 treatment periods
Drug: GSK2269557
Dry powder for oral inhalation (100 and 500 mcg /blister) once daily using DIKUS device. The doses of GSK2269557 planned for Part A are: 100 mcg, 500 mcg and 3000 mcg
Placebo Comparator: Placebo arm
The subjects will receive single dose of placebo in each treatment period of part A and repeat doses of placebo in Part B of the study.
Drug: Placebo
Dry powder for oral inhalation once daily using DIKUS device
Experimental: Part B GSK2269557 arm
The selection of total daily doses of GSK2269557 for Part B will anticipated to be the maximum well tolerated dose selected from Part A. The subjects will receive GSK2269557 in ratio of 3:1.with placebo. If the dose selected for Part B is not well tolerated on repeat dosing the dose may be reduced during Part B or given as divided doses.
Drug: GSK2269557
Dry powder for oral inhalation (100 and 500 mcg /blister) once daily using DIKUS device. The doses of GSK2269557 planned for Part A are: 100 mcg, 500 mcg and 3000 mcg

  Eligibility

Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Subjects who are current daily cigarette smokers. Must have smoked regularly in the 12-month period preceding the screening visit and have a pack history of >= 5 pack years (number of pack years = number of cigarettes per day/20 x number of years smoked
  • Normal spirometry (FEV1 >= 80% of predicted) at screening.
  • Single QTcF < 450 milliseconds (msec); or QTcF< 480 msec in subjects with Right Bundle Branch Block
  • Currently healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and cardiac testing. A subject with a clinical abnormality or laboratory parameters outside the reference range expected for them and the population being studied may be included only if the Investigator believes that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures or outcomes
  • Between 18 and 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 hysterectomy, bilateral oophorectomy or bilateral salpingectomy or postmenopausal defined as 12 months of spontaneous amenorrhea. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods f they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. 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.
  • Body weight >= 50 kilogram (kg) and body mass index (BMI) within the range 18 to 31 kg/meter^2 (inclusive).
  • Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form

Exclusion Criteria:

  • Subjects who are unable to produce a total weight of at least 0.100 grams (g) of selected sputum at screening
  • Subjects whose primary consumption of tobacco is via methods other than cigarettes (manufactured or self-rolled). Primary methods of tobacco consumption that are excluded include, but are not limited to pipes and cigars
  • Urinary cotinine levels at screening < 30 nanograms (ng)/mL
  • 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 (with the exception of Gilbert's syndrome or asymptomatic gallstones)
  • A history of congestive heart failure, coronary insufficiency or clinically significant cardiac arrhythmia that would contraindicate the subject's participation in the study
  • A positive pre-study drug/alcohol screen
  • A positive test for HIV antibody
  • 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 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits
  • The 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: 90 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
  • Unable to refrain from the use of prescription or non-prescription drugs (except simple analgesics), including vitamins, herbal and dietary supplements (including St John's Wort) within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and GlaxoSmithKline (GSK) Medical Monitor the medication will not interfere with the study procedures or compromise subject safety
  • The subject has received any type of vaccination within 4 weeks of their first dose of investigational product, or are expected to be vaccinated within 4 weeks after their last dose of investigational product
  • History of sensitivity to any of the study medications, or components thereof 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 90 day period
  • Unwillingness or inability to follow the procedures outlined in the protocol
  • Subject is mentally or legally incapacitated
  • Subjects who have asthma or a history of asthma (except in childhood and which has now remitted)
  • Unable to refrain from consumption of red wine, seville oranges, grapefruit or grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids from 7 days prior to the first and subsequent doses of study medication and until collection of the last PK sample for that study period
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01762878


Locations
United Kingdom
GSK Investigational Site
London, United Kingdom, NW10 7EW
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Additional Information:
Study Data/Documents: Clinical Study Report  This link exits the ClinicalTrials.gov site
Identifier: 116617
For additional information about this study please refer to the GSK Clinical Study Register
Statistical Analysis Plan  This link exits the ClinicalTrials.gov site
Identifier: 116617
For additional information about this study please refer to the GSK Clinical Study Register
Informed Consent Form  This link exits the ClinicalTrials.gov site
Identifier: 116617
For additional information about this study please refer to the GSK Clinical Study Register
Dataset Specification  This link exits the ClinicalTrials.gov site
Identifier: 116617
For additional information about this study please refer to the GSK Clinical Study Register
Annotated Case Report Form  This link exits the ClinicalTrials.gov site
Identifier: 116617
For additional information about this study please refer to the GSK Clinical Study Register
Study Protocol  This link exits the ClinicalTrials.gov site
Identifier: 116617
For additional information about this study please refer to the GSK Clinical Study Register
Individual Participant Data Set  This link exits the ClinicalTrials.gov site
Identifier: 116617
For additional information about this study please refer to the GSK Clinical Study Register

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01762878     History of Changes
Other Study ID Numbers: 116617
First Submitted: January 4, 2013
First Posted: January 8, 2013
Last Update Posted: July 13, 2017
Last Verified: July 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
URL: http://

Keywords provided by GlaxoSmithKline:
pharmacodynamics
pharmacokinetics
healthy volunteers
Pi3K-delta
GSK2269557
safety
dry powder inhaler

Additional relevant MeSH terms:
Lung Diseases
Chronic Disease
Pulmonary Disease, Chronic Obstructive
Respiratory Tract Diseases
Disease Attributes
Pathologic Processes
Lung Diseases, Obstructive