Last updated: 07/17/2024 17:15:37

Safety, tolerability and pharmacokinetics of single and repeat doses of GSK2292767 in healthy participants who smoke cigarettes

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GSK study ID
202062
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Clinicaltrials.gov ID
NCT03045887
See results summary
EudraCT ID
2016-003188-21
EU CT Number
Not applicable
Trial status
Study complete
Study complete
Overview
Eligibility
Locations
Study documents
Results summary
Plain language summaries
Additional information

Trial overview

Official title: A single-centre, double-blind (sponsor open), placebo controlled two part study to evaluate the safety, tolerability and pharmacokinetics of single and repeat doses of GSK2292767 as a dry powder in healthy participants who smoke cigarettes
Trial description: This study is the first administration of GSK2292767 to humans. The study will evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single and repeat inhaled doses of GSK2292767 in healthy smokers. This study is intended to provide sufficient confidence in the safety of the molecule and preliminary information on target engagement to allow progression to further repeat dose and proof of mechanism studies. This is a two part, single site, randomized, double-blind (sponsor open), placebo controlled study. Part A will consist of two 3-period interlocking cohorts to evaluate the safety, tolerability and pharmacokinetics of ascending single doses of GSK2292767 administered as a dry powder inhalation. Part B is planned to follow Part A and progression will be based on an acceptable safety, tolerability and pharmacokinetic profiles. Subjects will receive repeat doses of GSK2292767 once daily for 14 days during Part B.
Primary purpose:
Treatment
Trial design:
Crossover Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Allocation:
Randomized
Primary outcomes:

Part A: Number of participants with any Non-serious adverse event (nSAE) and any serious adverse event (SAE)

Timeframe: Up to 12 weeks

Part B: Number of participants with any AE and any SAE

Timeframe: Up to 4 weeks

Part A: Change from Baseline in systolic blood pressure (SBP) and diastolic blood pressure (DBP)

Timeframe: 30 minutes, 1, 6, 12 and 24 hours post-dose in each treatment period

Part B: Change from Baseline in SBP and DBP

Timeframe: Pre-dose on Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, 24 hours post-dose on Day 14

Part A: Change from Baseline in Heart rate

Timeframe: 30 minutes, 1, 6, 12 and 24 hours post-dose in each treatment period

Part B: Change from Baseline in Heart rate

Timeframe: Pre-dose on Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, 24 hours post-dose on Day 14

Part A: Change from Baseline in Respiratory rate

Timeframe: 30 minutes, 1, 6, 12 and 24 hours post-dose in each treatment period

Part B: Change from Baseline in Respiratory rate

Timeframe: Pre-dose on Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, 24 hours post-dose on Day 14

Part A: Change from Baseline in tympanic temperature

Timeframe: 30 minutes, 1, 6, 12 and 24 hours post-dose in each treatment period

Part B: Change from Baseline in tympanic temperature

Timeframe: Pre-dose on Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, 24 hours post-dose on Day 14

Part A: Maximal amount of air forcefully exhaled in 1 second (FEV1)

Timeframe: Day 1 (pre-dose and 1 hour)

Part B: Maximal amount of air forcefully exhaled in 1 second (FEV1)

Timeframe: Up to Day 14

Part A: Forced vital capacity (FVC)

Timeframe: Day 1 (pre-dose and 1 hour)

Part B: Forced vital capacity (FVC)

Timeframe: Day 1 (pre-dose and 1 hour)

Part A: Number of participants with electrocardiogram (ECG) abnormalities

Timeframe: Day 1 of each treatment period

Part B: Number of participants with ECG abnormalities

Timeframe: Pre-dose on Days 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14, 24 hours post-dose on Day 14

Part A: Number of participants with clinical chemistry values of potential clinical importance criteria (PCC)

Timeframe: 24 hours post-dose in each treatment period.

Part B: Number of participants with clinical chemistry values of PCC

Timeframe: Pre-dose on Days 2, 4, 6, 8, 10, 12, and 14, 24 hours post-dose on Day 14

Part A: Number of participants with hematology values of PCC

Timeframe: 24 hours post-dose in each treatment period

Part B: Number of participants with hematology values of PCC

Timeframe: Pre-dose on Days 2, 4, 6, 8, 10, 12, and 14, 24 hours post-dose on Day 14

Secondary outcomes:

Part A: Area under the plasma drug concentration versus time curve (AUC) from zero to time t (AUC [0 to t]), AUC from zero to 24 hours (AUC [0 to 24]) and AUC from zero to infinity (AUC [0 to inf]) of GSK2292767

Timeframe: Pre-dose (5 minutes (min), 30 min, 45 min, 1 hour (hr), 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr post dose in each of the 3 treatment periods

Part B: AUC (0 to t), AUC (0 to 24) and AUC (0 to inf) of GSK2292767

Timeframe: Days 1 and 14

Part A: Maximum observed plasma drug concentration (Cmax) of GSK2292767

Timeframe: Pre-dose (5 min, 30 min, 45 min, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr post dose in each of the 3 treatment periods

Part B: Cmax of GSK2292767

Timeframe: Days 1 and 14

Part A: Time to maximum observed plasma drug concentration (Tmax) of GSK2292767

Timeframe: Pre-dose (5 min, 30 min, 45 min, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr post dose in each of the 3 treatment periods

Part B: Tmax of GSK2292767

Timeframe: Days 1 and 14

Part A: terminal half-life (T1/2) of GSK2292767

Timeframe: Pre-dose (5 min, 30 min, 45 min, 1 hr, 2 hr, 3 hr, 4 hr, 6 hr, 8 hr, 12 hr, and 24 hr post dose in each of the 3 treatment periods

Part B: T1/2 of GSK2292767

Timeframe: Days 1 and 14

Part A: trough concentrations (Ctau) of GSK2292767

Timeframe: 24 hr post dose in each of the 3 treatment periods

Part B: Ctau of GSK2292767

Timeframe: Days 1 and 14

Part B: Concentration of GSK2292767 in bronchoalveolar lavage (BAL)

Timeframe: Day 15

Part B: Concentration of GSK2292767 in lung Epithelial lining fluid (ELF)

Timeframe: Day 15

Interventions:
  • Drug: GSK2292767 50 μg
  • Drug: GSK2292767 500 μg
  • Drug: Placebo
    • Enrollment:
    38
    Primary completion date:
    2017-11-08
    Observational study model:
    Not applicable
    Time perspective:
    Not applicable
    Clinical publications:
    Malcolm Begg, Chris Edwards, J. Nicole Hamblin, Eleni Pefani, Robert Wilson, Jane Gilbert, Giovanni Vitulli, David Mallett, Josie Morrell, Martin I Hingle, Sorif Uddin, Filzah Ehtesham, Miriam Marotti, Andrew Harrell, Carla Newman, Disala Fernando, Jonathan Clark, Anthony Cahn, Edith M Hessel. Translation of inhaled drug optimisation strategies into clinical pharmacokinetics and pharmacodynamics using GSK2292767A; a novel inhaled PI3K[delta] inhibitor. J Pharmacol Exp Ther. 2019; DOI: 10.1124/jpet.119.257311 PMID: 30940692
    Medical condition
    Asthma
    Product
    GSK2292767
    Collaborators
    Not applicable
    Study date(s)
    February 2017 to August 2017
    Type
    Interventional
    Phase
    1

    Participation criteria

    Sex
    Female & Male
    Age
    18 - 50 years
    Accepts healthy volunteers
    Yes
    • Participant must be 18 to 50 years of age inclusive, at the time of signing the informed consent
    • Participants who are overtly healthy as determined by medical evaluation including (medical history, physical examination, laboratory tests, and cardiac monitoring). A participant 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
    • History or presence of current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, haematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatment; or interfering with the interpretation of data
    • Abnormal blood pressure as determined by the investigator
    Inclusion and exclusion criteria
    Inclusion criteria:
    • Participant must be 18 to 50 years of age inclusive, at the time of signing the informed consent
    • Participants who are overtly healthy as determined by medical evaluation including (medical history, physical examination, laboratory tests, and cardiac monitoring). A participant 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
    • Participants who are current daily cigarette smokers (manufactured and self-rolled). Must have smoked regularly in the 12-month period preceding the screening visit
    • Normal spirometry (FEV1 >=80% of predicted) at screening
    • Body weight >=50 kilograms (kg) and body mass index (BMI) within the range 18 to 31 kg/square meter (m^2) (inclusive)

      • Male and female

      • Male participants: A male participant must agree to use contraception as detailed in the protocol during the treatment period and for at least from the time of first dose of study medication until at least 55 (5x11) hours plus an additional 90 days after the last dose of study medication and refrain from donating sperm during this period. GSK2292767 has a predicted half-life of approximately 11 hours
      • Female participants: A female participant is eligible to participate if she is not pregnant, not breastfeeding, and not a woman of childbearing potential (WOCBP)
    • Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol
    Exclusion criteria:
    • History or presence of current cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, haematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study treatment; or interfering with the interpretation of data
    • Abnormal blood pressure as determined by the investigator
    • Alanine transaminase (ALT) >1.5xupper limit of normal (ULN)
    • Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
    • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
    • Average corrected QT interval by Fridericia's formula (QTcF) >450 milliseconds (msec) (based on triplicate ECGs)
    • Participants who have asthma or a history of asthma (except in childhood and which has now remitted)
    • Past or intended use of over-the-counter or prescription medication including herbal medications within 14 days prior to dosing. Specific concomitant medications listed in protocol may be allowed
    • Live vaccine(s) within 1 month prior to screening, or plans to receive such vaccines during the study
    • Participation in the study would result in loss of blood or blood products in excess of 500 milliliters (mL) within 56 days
    • Exposure to more than 4 new chemical entities within 12 months prior to the first dosing day
    • Current enrolment or past participation within the last 90 days of exposure to any other clinical study involving an investigational study treatment or any other type of medical research
    • Presence of Hepatitis B surface antigen (HBsAg) at screening Positive Hepatitis C antibody test result at screening
    • Positive Hepatitis C ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study treatment
    • Positive pre-study drug/alcohol screen
    • Positive human immunodeficiency virus (HIV) antibody test
    • Regular use of known drugs of abuse
    • Regular alcohol consumption within 3 months prior to the study defined as: An average weekly intake of >14 units for males and females. One unit is equivalent to 8 grams (g) of alcohol: a half-pint (approximately 240 mL of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits
    • Sensitivity to any of the study treatments, or components thereof, or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study
    • Participants who are unable to produce a total weight of at least 100 milligrams (mg) of selected sputum during sputum induction at screening
    • Participants 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

    Trial location(s)

    Location
    Status
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    Location
    GSK Investigational Site
    Cambridge, United Kingdom, CB2 2GG
    Status
    Study Complete
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    Study documents

    Protocol
    Available language(s): English
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    Statistical analysis plan
    Available language(s): English
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    If you wish to request for full study report, please contact - [email protected]

    Results overview

    Results posted on ClinicalTrials.gov

    Recruitment status
    Study complete
    Actual primary completion date
    2017-11-08
    Actual study completion date
    2017-16-08

    Plain language summaries

    Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.

    Additional information about the trial

    Additional information
    Not applicable
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