Safety, Tolerability and Pharmacokinetics of Single and Repeat Doses of GSK2292767 in Healthy Participants Who Smoke Cigarettes

Asthma Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03045887
• Other study ID #: 202062
• Secondary ID: 2016-003188-21
• Status: Completed
• Phase: Phase 1
• Start date: February 6, 2017
• Est. completion date: August 16, 2017

Study information

• Verified date: July 2019
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 38
• Est. completion date: August 16, 2017
• Est. primary completion date: August 11, 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

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

Related Conditions & MeSH terms

• Asthma

Intervention

Drug:
• GSK2292767 50 µg
GSK2292767 50 µg blended with lactose and magnesium stearate per blister as powder for inhalation
• GSK2292767 500 µg
GSK2292767 500 µg blended with lactose and magnesium stearate per blister as powder for inhalation
• Placebo
Lactose as powder for inhalation

Locations

Country	Name	City	State
United Kingdom	GSK Investigational Site	Cambridge

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Country where clinical trial is conducted

United Kingdom, 

References & Publications (1)

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 d Inhibitor. J Pharmacol Exp Ther. 2019 Jun;369(3):443-453. doi: 10.1124/jpet.119.257311. Epub 2019 Apr 2. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part A: Number of Participants With Any Non-serious Adverse Event (nSAE) and Any Serious Adverse Event (SAE)	An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or all events of possible drug-induced liver injury with hyperbilirubinemia were categorized as SAE. Participants with 5 percent nSAEs and SAEs has been reported.	Up to 12 weeks
Primary	Part B: Number of Participants With Any AE and Any SAE	An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment or all events of possible drug-induced liver injury with hyperbilirubinemia were categorized as SAE. Participants with 5 percent nSAEs and SAEs has been reported.	Up to 4 weeks
Primary	Part A: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)	Blood pressure in part A was assessed in a semi supine position with a completely automated device. SBP and DBP measurements were preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as the latest pre-dose assessment. Change from Baseline was defined as the value at indicated time point minus Baseline value.	Baseline, 30 minutes, 1, 6, 12 and 24 hours post-dose in each treatment period
Primary	Part B: Change From Baseline in SBP and DBP	Blood pressure in part B were assessed in semi supine position with a completely automated device. SBP and DBP preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as measurements done on Day -1. Change from Baseline was defined as the value at indicated time point minus Baseline value.	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
Primary	Part A: Change From Baseline in Heart Rate	Heart rate in part A was assessed in a semi supine position with a completely automated device. Heart rate measurement was preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as latest pre-dose measurement. Change from Baseline was defined as the value at indicated time point minus Baseline value.	Baseline, 30 minutes, 1, 6, 12 and 24 hours post-dose in each treatment period
Primary	Part B: Change From Baseline in Heart Rate	Heart rate in part B was assessed in a semi supine position with a completely automated device. Heart rate measurement was preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as latest pre-dose measurement. Change from Baseline was defined as the value at indicated time point minus Baseline value.	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
Primary	Part A: Change From Baseline in Respiratory Rate	Respiratory rate in part A was assessed in a semi supine position after 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as measurements done on Day -1. Change from Baseline was defined as the value at indicated time point minus Baseline value. Baseline was defined as latest pre-dose measurement. Change from Baseline was defined as the value at indicated time point minus Baseline value.	Baseline, 30 minutes, 1, 6, 12 and 24 hours post-dose in each treatment period
Primary	Part B: Change From Baseline in Respiratory Rate	Respiratory rate in part B was assessed in a semi supine position after 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as measurements done on Day -1. Change from Baseline was defined as the value at indicated time point minus Baseline value. Baseline was defined as latest pre-dose measurement. Change from Baseline was defined as the value at indicated time point minus Baseline value.	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
Primary	Part A: Change From Baseline in Tympanic Temperature	Tympanic temperature in part A was assessed in semi supine position after 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as measurements done on Day -1. Change from Baseline was defined as the value at indicated time point minus Baseline value. Baseline was defined as latest pre-dose measurement. Change from Baseline was defined as the value at indicated time point minus Baseline value.	Baseline, 30 minutes, 1, 6, 12 and 24 hours post-dose in each treatment period
Primary	Part B: Change From Baseline in Tympanic Temperature	Tympanic temperature in part B was assessed in semi supine position after 5 minutes of rest for the participant in a quiet setting without distractions. Baseline was defined as measurements done on Day -1. Change from Baseline was defined as the value at indicated time point minus Baseline value. Baseline was defined as latest pre-dose measurement. Change from Baseline was defined as the value at indicated time point minus Baseline value.	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
Primary	Part A: Maximal Amount of Air Forcefully Exhaled in 1 Second (FEV1)	FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. FEV1 was measured using spirometry at the indicated time. FEV1 measurements were repeated until three technically acceptable measurements (within 150 milliliter [mL] of each other) were made. Data for FEV1 for part A is presented here.	Day 1 (pre-dose and 1 hour)
Primary	Part B: Maximal Amount of Air Forcefully Exhaled in 1 Second (FEV1)	FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. FEV1 was measured using spirometry at the indicated time. Existing spirometry equipment was used. FEV1 measurements were repeated until three technically acceptable measurements (within 150 mL of each other) were made. Data for FEV1 for part B is presented here.	Up to Day 14
Primary	Part A: Forced Vital Capacity (FVC)	FVC is a measure of lung function and is defined as total amount of air that can be exhaled during FEV1 test. FVC was planned to measured using spirometry. The FVC need to be normal at screening and is part of the Forced Expiratory ratio (FEV1/FVC) which should lie between 0.7-0.8 to indicate no chronic obstruction or restriction. The FVC was therefore only used at screening and requires no ongoing analysis during the study. All other indications of obstruction in the study, e.g. paradoxical bronchospasm was provided by the FEV1. The FVC therefore require no analysis.	Day 1 (pre-dose and 1 hour)
Primary	Part B: Forced Vital Capacity (FVC)	FVC is a measure of lung function and is defined as total amount of air that can be exhaled during FEV1 test. FVC was planned to measured using spirometry. The FVC need to be normal at screening and is part of the Forced Expiratory ratio (FEV1/FVC) which should lie between 0.7-0.8 to indicate no chronic obstruction or restriction. The FVC was therefore only used at screening and requires no ongoing analysis during the study. All other indications of obstruction in the study, e.g. paradoxical bronchospasm was provided by the FEV1. The FVC therefore require no analysis.	Day 1 (pre-dose and 1 hour)
Primary	Part A: Number of Participants With Electrocardiogram (ECG) Abnormalities	Triplicate/Single 12-lead ECG was obtained using an automated ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTFc intervals. Number of participants with abnormal clinically significant and abnormal-not clinically significant values at any time post-Baseline is presented.	Day 1 of each treatment period
Primary	Part B: Number of Participants With ECG Abnormalities	Triplicate/Single 12-lead ECG was obtained using an automated ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTFc intervals. Number of participants with abnormal clinically significant and abnormal-not clinically significant values at any time post-Baseline is presented.	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
Primary	Part A: Number of Participants With Clinical Chemistry Values of Potential Clinical Importance Criteria (PCC)	Number of participants with clinical chemistry values that changed from normal to high or low in part A are presented. Chemistry parameters for which PCC values were identified were: Alkaline Phosphatase, Alanine Amino Transferase, aspartate aminotransferase, Total Bilirubin, calcium, glucose, potassium and Sodium.	24 hours post-dose in each treatment period.
Primary	Part B: Number of Participants With Clinical Chemistry Values of PCC	Number of participants with clinical chemistry values that changed from normal to high or low in part B are presented. Chemistry parameters for which PCC values were identified were: Alkaline Phosphatase, Alanine Amino Transferase, aspartate aminotransferase, Total Bilirubin, calcium, glucose, potassium and Sodium. Only participants with data available at specified time points were analyzed (represented by n=X in category titles)	Pre-dose on Days 2, 4, 6, 8, 10, 12, and 14, 24 hours post-dose on Day 14
Primary	Part A: Number of Participants With Hematology Values of PCC	Number of participants with hematology parameters of PCC which shifted from normal to high in part A are presented. Hematology parameters for which PCC values were identified were: Hemoglobin, Hematocrit, Lymphocytes, Total Neutrophils, Platelet count and White Blood Cell (WBC) Count. Only those participants with data available at the specified time points were analyzed (represented by n=X in category titles)	24 hours post-dose in each treatment period
Primary	Part B: Number of Participants With Hematology Values of PCC	Number of participants with hematology parameters of PCC which shifted from normal to high in part B are presented. Hematology parameters for which PCC values were identified were: Hemoglobin, Hematocrit, Lymphocytes, Total Neutrophils, Platelet count and WBC count	Pre-dose on Days 2, 4, 6, 8, 10, 12, and 14, 24 hours post-dose on Day 14
Secondary	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	Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Data for AUC (0 to t), AUC (0 to 24) and AUC (0 to inf) of GSK2292767 for part A is presented. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). Pharmacokinetic population comprised of participants in the 'All participant' population for whom a pharmacokinetic sample was obtained and analyzed.	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
Secondary	Part B: AUC (0 to t), AUC (0 to 24) and AUC (0 to Inf) of GSK2292767	Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Data for AUC (0 to t), AUC (0 to 24) and AUC (0 to inf) of GSK2292767 for part B is presented. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).	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
Secondary	Part A: Maximum Observed Plasma Drug Concentration (Cmax) of GSK2292767	Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Five min post dose concentrations on Days 2-13 were assumed to be the Cmax values. Data for Cmax of GSK2292767 for part A is presented. Cmax is defined as maximum observed plasma concentration of GSK2292767.	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
Secondary	Part B: Cmax of GSK2292767	Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Five minute post dose concentrations on Days 2-13 were assumed to be the Cmax values. Data for Cmax of GSK2292767 for part B is presented.	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
Secondary	Part A: Time to Maximum Observed Plasma Drug Concentration (Tmax) of GSK2292767	Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Data for Tmax of GSK2292767 for part A is presented.	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
Secondary	Part B: Tmax of GSK2292767	Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Data for Tmax of GSK2292767 for part B is presented.	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
Secondary	Part A: Terminal Half-life (T1/2) of GSK2292767	Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Data for T1/2 of GSK2292767 for part A is presented. T1/2 is defined as the time required for one half of the total amount of a particular substance in a biological system to be degraded by biological processes. Only those participants with data available at the specified time points were analyzed.	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
Secondary	Part B: T1/2 of GSK2292767	Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Data for T1/2 of GSK2292767 for part B is presented. T1/2 was defined as the time required for one half of the total amount of a particular substance in a biological system to be degraded by biological processes. Only those participants with data available at the specified time points were analyzed.	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
Secondary	Part A: Trough Concentrations (Ctau) of GSK2292767	Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Data for Ctau of GSK2292767 for part A is presented. Ctau is defined as the lowest concentration reached by a drug before the next dose is administered.	24 hr post dose in each of the 3 treatment periods
Secondary	Part B: Ctau of GSK2292767	Blood samples were collected for pharmacokinetic analysis of GSK2292767 at the specified time points. Data for Ctau of GSK2292767 for part B is presented. Ctau is defined as the lowest concentration reached by a drug before the next dose is administered. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles).	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
Secondary	Part B: Concentration of GSK2292767 in Bronchoalveolar Lavage (BAL)	BAL samples were collected by bronchoscopy.	Day 15
Secondary	Part B: Concentration of GSK2292767 in Lung Epithelial Lining Fluid (ELF)	ELF from the lung was extracted from BAL samples. ELF drug concentration was calculated as BAL fluid drug concentration multiplied by dilution factor where dilution factor = Plasma urea (pre-bronchoscopy) divided by BAL urea. NA indicates data not available. Only participants with data available at specified time points were analyzed (represented by n=X in category titles).	Day 15