Clinical trial NCT03045887: Safety, Tolerability and Pharmacokinetics of Single and Repeat Doses of GSK2292767 in Healthy Participants Who Smoke Cigarettes
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Asthma
Keywords: repeat dose
GSK2292767
smoke
tolerability
safety
dry powder inhalation
pharmacokinetics
single dose
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2017-02-08
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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

Primary outcomes:
measure: Part A: Number of Participants With Any Non-serious Adverse Event (nSAE) and Any Serious Adverse Event (SAE)
timeFrame: Up to 12 weeks
measure: Part B: Number of Participants With Any AE and Any SAE
timeFrame: Up to 4 weeks
measure: Part A: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline, 30 minutes, 1, 6, 12 and 24 hours post-dose in each treatment period
measure: Part B: Change From Baseline in SBP and DBP
timeFrame: Baseline, 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
measure: Part A: Change From Baseline in Heart Rate
timeFrame: Baseline, 30 minutes, 1, 6, 12 and 24 hours post-dose in each treatment period
measure: Part B: Change From Baseline in Heart Rate
timeFrame: Baseline, 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
measure: Part A: Change From Baseline in Respiratory Rate
timeFrame: Baseline, 30 minutes, 1, 6, 12 and 24 hours post-dose in each treatment period
measure: Part B: Change From Baseline in Respiratory Rate
timeFrame: Baseline, 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
measure: Part A: Change From Baseline in Tympanic Temperature
timeFrame: Baseline, 30 minutes, 1, 6, 12 and 24 hours post-dose in each treatment period
measure: Part B: Change From Baseline in Tympanic Temperature
timeFrame: Baseline, 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
measure: Part A: Maximal Amount of Air Forcefully Exhaled in 1 Second (FEV1)
timeFrame: Day 1 (pre-dose and 1 hour)
measure: Part B: Maximal Amount of Air Forcefully Exhaled in 1 Second (FEV1)
timeFrame: Up to Day 14
measure: Part A: Forced Vital Capacity (FVC)
timeFrame: Day 1 (pre-dose and 1 hour)
measure: Part B: Forced Vital Capacity (FVC)
timeFrame: Day 1 (pre-dose and 1 hour)
measure: Part A: Number of Participants With Electrocardiogram (ECG) Abnormalities
timeFrame: Day 1 of each treatment period
measure: 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
measure: Part A: Number of Participants With Clinical Chemistry Values of Potential Clinical Importance Criteria (PCC)
timeFrame: 24 hours post-dose in each treatment period.
measure: 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
measure: Part A: Number of Participants With Hematology Values of PCC
timeFrame: 24 hours post-dose in each treatment period
measure: 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:
measure: 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
measure: Part B: AUC (0 to t), AUC (0 to 24) and AUC (0 to Inf) of GSK2292767
timeFrame: Pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 1; pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 14
measure: 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
measure: Part B: Cmax of GSK2292767
timeFrame: Pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 1; pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 14
measure: 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
measure: Part B: Tmax of GSK2292767
timeFrame: Pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 1; pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 14
measure: 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
measure: Part B: T1/2 of GSK2292767
timeFrame: Pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 1; pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 14
measure: Part A: Trough Concentrations (Ctau) of GSK2292767
timeFrame: 24 hr post dose in each of the 3 treatment periods
measure: Part B: Ctau of GSK2292767
timeFrame: Pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 1; pre-dose, 5 minutes, 30 minutes, 45 minutes, 1, 2, 3, 4, 6, 8 and 12hours post dose on Day 14
measure: Part B: Concentration of GSK2292767 in Bronchoalveolar Lavage (BAL)
timeFrame: Day 15
measure: Part B: Concentration of GSK2292767 in Lung Epithelial Lining Fluid (ELF)
timeFrame: Day 15
Other outcomes:
Locations:
city: Cambridge
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Begg M, Edwards CD, Hamblin JN, Pefani E, Wilson R, Gilbert J, Vitulli G, Mallett D, Morrell J, Hingle MI, Uddin S, Ehtesham F, Marotti M, Harrell A, Newman CF, Fernando D, Clark J, Cahn A, Hessel EM. Translation of Inhaled Drug Optimization Strategies into Clinical Pharmacokinetics and Pharmacodynamics Using GSK2292767A, a Novel Inhaled Phosphoinositide 3-Kinase delta Inhibitor. J Pharmacol Exp Ther. 2019 Jun;369(3):443-453. doi: 10.1124/jpet.119.257311. Epub 2019 Apr 2.