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

NCT03045887 | Completed Phase 1 Results

• 2 other identifiers: 2020622016-003188-21
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 1

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.

Conditions

Asthma

Keywords

repeat dose; GSK2292767; smoke; tolerability; safety; dry powder inhalation; pharmacokinetics; single dose

Outcome Measures

Primary Outcomes (20)

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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

• 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)

• 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

• 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)

• 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)

• 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

• 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

• 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.

• 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

• 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

• 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 Outcomes (12)

• 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

  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

  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

• Part A: Maximum Observed Plasma Drug Concentration (Cmax) 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

• Part B: Cmax of GSK2292767

  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

• Part A: Time to Maximum Observed Plasma Drug Concentration (Tmax) 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

Study Arms (10)

Part A Cohort 1: Placebo- GSK2292767 (GSK) 200 µg-GSK 1000 µg

EXPERIMENTAL

Subjects will receive an inhaled single dose of placebo in Period 1, GSK2292767 200 µg in Period 2, and GSK2292767 1000 µg in Period 3. There will be a washout of approximately 4 weeks between doses.

Drug: GSK2292767 50 μg; Drug: GSK2292767 500 μg; Drug: Placebo

Part A Cohort 1: GSK 50 µg-Placebo-GSK 1000 µg

EXPERIMENTAL

Subjects will receive an inhaled single dose of GSK2292767 50 µg in Period 1, placebo in Period 2, and GSK2292767 1000 µg in Period 3. There will be a washout of approximately 4 weeks between doses.

Drug: GSK2292767 50 μg; Drug: GSK2292767 500 μg; Drug: Placebo

Part A Cohort 1: GSK 50 µg- GSK 200 µg-Placebo

EXPERIMENTAL

Subjects will receive an inhaled single dose of GSK2292767 50 µg in Period 1, GSK2292767 200 µg in Period 2, and placebo in Period 3. There will be a washout of approximately 4 weeks between doses.

Drug: GSK2292767 50 μg; Drug: Placebo

Part A Cohort 1: GSK 50 µg-GSK 200 µg-GSK 1000 µg

EXPERIMENTAL

Subjects will receive an inhaled single dose of GSK2292767 50 µg in Period 1, GSK2292767 200 µg in Period 2, and GSK2292767 1000 µg in Period 3. There will be a washout of approximately 4 weeks between doses.

Drug: GSK2292767 50 μg; Drug: GSK2292767 500 μg

Part A Cohort 2: Placebo-GSK 500 µg-GSK 2000 µg

EXPERIMENTAL

Subjects will receive an inhaled single dose of placebo in Period 1, GSK2292767 500 µg in Period 2, and GSK2292767 2000 µg in Period 3. There will be a washout of approximately 4 weeks between doses.

Drug: GSK2292767 500 μg; Drug: Placebo

Part A Cohort 2: GSK 100 µg-Placebo- GSK 2000 µg

EXPERIMENTAL

Subjects will receive an inhaled single dose of GSK2292767 100 µg in Period 1, placebo in Period 2, and GSK2292767 2000 µg in Period 3. There will be a washout of approximately 4 weeks between doses.

Drug: GSK2292767 50 μg; Drug: GSK2292767 500 μg; Drug: Placebo

Part A Cohort 2: GSK 100 µg-GSK 500 µg-Placebo

EXPERIMENTAL

Subjects will receive an inhaled single dose of GSK2292767 100 µg in Period 1, GSK2292767 500 µg in Period 2 and placebo in Period 3. There will be a washout of approximately 4 weeks between doses.

Drug: GSK2292767 50 μg; Drug: GSK2292767 500 μg; Drug: Placebo

Part A Cohort 2: GSK 100 µg-GSK 500 µg-GSK 2000 µg

EXPERIMENTAL

Subjects will receive an inhaled single dose of GSK2292767 100 µg in Period 1, GSK2292767 500 µg in Period 2, GSK2292767 2000 µg in Period 3. There will be a washout of approximately 4 weeks between doses.

Drug: GSK2292767 50 μg; Drug: GSK2292767 500 μg

Part B: GSK

EXPERIMENTAL

Subjects will receive inhaled repeat dose of GSK2292767 2000 µg once daily for 14 days.

Drug: GSK2292767 500 μg

Part B: Placebo

EXPERIMENTAL

Subjects will receive inhaled repeat dose of placebo once daily for 14 days.

Drug: Placebo

Interventions

GSK2292767 50 μg DRUG

GSK2292767 50 μg blended with lactose and magnesium stearate per blister as powder for inhalation

Part A Cohort 1: GSK 50 µg- GSK 200 µg-Placebo; Part A Cohort 1: GSK 50 µg-GSK 200 µg-GSK 1000 µg; Part A Cohort 1: GSK 50 µg-Placebo-GSK 1000 µg; Part A Cohort 1: Placebo- GSK2292767 (GSK) 200 µg-GSK 1000 µg; Part A Cohort 2: GSK 100 µg-GSK 500 µg-GSK 2000 µg; Part A Cohort 2: GSK 100 µg-GSK 500 µg-Placebo; Part A Cohort 2: GSK 100 µg-Placebo- GSK 2000 µg

GSK2292767 500 μg DRUG

GSK2292767 500 μg blended with lactose and magnesium stearate per blister as powder for inhalation

Part A Cohort 1: GSK 50 µg-GSK 200 µg-GSK 1000 µg; Part A Cohort 1: GSK 50 µg-Placebo-GSK 1000 µg; Part A Cohort 1: Placebo- GSK2292767 (GSK) 200 µg-GSK 1000 µg; Part A Cohort 2: GSK 100 µg-GSK 500 µg-GSK 2000 µg; Part A Cohort 2: GSK 100 µg-GSK 500 µg-Placebo; Part A Cohort 2: GSK 100 µg-Placebo- GSK 2000 µg; Part A Cohort 2: Placebo-GSK 500 µg-GSK 2000 µg; Part B: GSK

Placebo DRUG

Lactose as powder for inhalation

Part A Cohort 1: GSK 50 µg- GSK 200 µg-Placebo; Part A Cohort 1: GSK 50 µg-Placebo-GSK 1000 µg; Part A Cohort 1: Placebo- GSK2292767 (GSK) 200 µg-GSK 1000 µg; Part A Cohort 2: GSK 100 µg-GSK 500 µg-Placebo; Part A Cohort 2: GSK 100 µg-Placebo- GSK 2000 µg; Part A Cohort 2: Placebo-GSK 500 µg-GSK 2000 µg; Part B: Placebo

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Cambridge, CB2 2GG, United Kingdom

Location

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

  PMID: 30940692 BACKGROUND

MeSH Terms

Conditions

Asthma

Interventions

GSK2292767

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 3, 2017
• First Posted: February 8, 2017
• Study Start: February 6, 2017
• Primary Completion: August 11, 2017
• Study Completion: August 16, 2017
• Last Updated: July 24, 2019
• Results First Posted: May 28, 2019

Record last verified: 2019-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

GB (1)