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A Study to Evaluate the Safety, Efficacy and Changes in Induced Sputum and Blood Biomarkers Following Daily Repeat Doses of Inhaled GSK2269557 in Chronic Obstructive Pulmonary Disease (COPD) Subjects With Acute Exacerbation

Primary Purpose

Pulmonary Disease, Chronic Obstructive

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

GSK2269557

Placebo

DISKUS

ELLIPTA

About this trial

This is an interventional treatment trial for Pulmonary Disease, Chronic Obstructive focused on measuring double-blind, PI3Kdelta, GSK2269557, exacerbation, Chronic Obstructive Pulmonary Disease, randomised, placebo-controlled

Eligibility Criteria

40 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Between 40 and 80 years of age inclusive, at the time of signing the informed consent.
The subject has a confirmed and established diagnosis of COPD, as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for at least 6 months prior to entry.
The subject is able to produce >100 milligram (mg) of sputum at screening for processing, (ie, total weight of sputum plugs).
The subject has a post-bronchodilator FEV1/FVC <0.7 and FEV1 <=80 % of predicted.
Disease severity: Acute exacerbation of COPD requiring an escalation in therapy to include both corticosteroid and antibiotics. Acute exacerbation to be confirmed by an experienced physician and represent a recent change in at least two major and one minor symptoms, one major and two minor symptoms, or all 3 major symptoms. Major symptoms: Subjective increase in dyspnea; Increase in sputum volume; Change in sputum colour. Minor symptoms: Cough; Wheeze; Sore throat
The subject is a smoker or an ex-smoker with a smoking history of at least 10 pack years (pack years = [cigarettes per day smoked/20 x number of years smoked]).
Body weight >= 45 kilogram (kg) and body mass index (BMI) within the range 16 to 35 kilogram per meter square (kg/m^2) (inclusive)
Male
Female subject: is eligible to participate if she is not pregnant (as confirmed by a negative urine human chorionic gonadotrophin [hCG] test), not lactating, and at least one of the following conditions applies: (1)Non-reproductive potential defined as: Pre-menopausal females with one of the following: Documented tubal ligation; Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion; Hysterectomy; Documented Bilateral Oophorectomy. Postmenopausal defined as 12 months of spontaneous amenorrhea. Females whose menopausal status is in doubt will be required to use, or have been using, one of the highly effective contraception methods as specified below from 30 days prior to the first dose of study medication and until completion of the follow-up visit. 2)Reproductive potential and agrees to follow one of the options listed below in the GlaxoSmithKline (GSK) Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) requirements from 30 days prior to the first dose of study medication and until completion of the follow-up visit. GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in FRP. This list does not apply to FRP with same sex partners, when this is their preferred and usual lifestyle or for subjects who are and will continue to be abstinent from penile-vaginal intercourse on a long term and persistent basis. 1) Contraceptive subdermal implant that meets GSK standard criteria including a <1% rate of failure per year, as stated in the product label. 2) Intrauterine device or intrauterine system that meets GSK standard criteria including a <1% rate of failure per year, as stated in the product label. 3) Oral Contraceptive, either combined or progestogen alone. 4) Injectable progestogen. 5) Contraceptive vaginal ring. 6) Percutaneous contraceptive patches. 7) Male partner sterilization with documentation of azoospermia prior to the female subject's entry into the study, and this male is the sole partner for that subject. 8) Male condom combined with a vaginal spermicide (foam, gel, film, cream, or suppository). These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception. Specific inclusion criteria for Male subjects with female partners of reproductive potential is outlined below: Male subjects with female partners of child bearing potential must comply with the following contraception requirements from the time of first dose of study medication until after the completion of the follow up visit. 1) Vasectomy with documentation of azoospermia. 2) Male condom plus partner use of one of the contraceptive options below: Contraceptive subdermal implant that meets GSK standard criteria including a <1% rate of failure per year, as stated in the product label. Intrauterine device or intrauterine system that meets GSK standard criteria including a <1% rate of failure per year, as stated in the product label. Oral Contraceptive, either combined or progestogen alone. Injectable progestogen. Contraceptive vaginal ring. Percutaneous contraceptive patches. These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception.
Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.

Exclusion Criteria:

To avoid recruitment of subjects with a severe COPD exacerbation, the presence of any one of the following severity criteria will render the subject ineligible for inclusion in the study: Need for invasive mechanical ventilation (short term [<48 hour] Non-invasive ventilation [NIV] or continuous positive airway pressure [CPAP] is acceptable); Haemodynamic instability or clinically significant heart failure; Confusion; Clinically significant pneumonia, identified by chest X-ray at screening, and as judged by the Investigator.
Subjects who have current medical conditions or diseases that are not well controlled and, which as judged by the Investigator, may affect subject safety or influence the outcome of the study. (Note: Patients with adequately treated and well controlled concurrent medical conditions (e.g. hypertension or noninsulin-dependent diabetes mellitus [NIDDM]) are permitted to be entered into the study).
Subject has a diagnosis of active tuberculosis, lung cancer, clinically overt bronchiectasis, pulmonary fibrosis, asthma or any other respiratory condition that might, in the opinion of the investigator, compromise the safety of the subject or affect the interpretation of the results.
ALT >2xupper limit of normal (ULN) and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the exclusion criteria, outside of the reference range for the population being studied may be included if the Investigator [in consultation with the GSK Medical Monitor if required] documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones)
ECG indicative of an acute cardiac event (e.g. Myocardial Infarction) or demonstrating a clinically significant arrhythmia requiring treatment.
QTcF > 450 msec or QTcF > 480 msec in subjects with Bundle Branch Block, based on single QTcF value.
Subjects who have undergone lung volume reduction surgery.
Subject is currently on chronic treatment with macrolides or long term antibiotics.
Subject is being treated with long term oxygen therapy (LTOT) (>15 hours/day).
The subject has been on chronic treatment with anti-Tumour Necrosis Factor (anti-TNF), or any other immunosuppressive therapy (except corticosteroid) within 60 days prior to dosing
History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >28 units for males or >21 units for females. One unit is equivalent to 8 gram (g) of alcohol: a half-pint (~240 milliliter [mL]) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
History of sensitivity to any of the study medications, or components thereof (such as lactose) or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
A known (historical) positive test for human immunodeficiency virus (HIV) antibody.
Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. NOTE: Because of the short window for screening, treatment with GSK2269557 may start before receiving the result of the hepatitis tests. If subsequently the test is found to be positive, the subject may be withdrawn, as judged by the Principal Investigator in consultation with the Medical Monitor.
Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 56 days.
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: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer).
Exposure to more than 4 investigational medicinal products within 12 months prior to the first dosing day.

Sites / Locations

GSK Investigational Site
GSK Investigational Site
GSK Investigational Site
GSK Investigational Site
GSK Investigational Site
GSK Investigational Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Arm Label

GSK2269557 1000 microgram (mcg)

Placebo via DISKUS

GSK2269557 700 mcg

Placebo via ELLIPTA

Arm Description

Subjects will receive 2 inhalations of GSK2269557 (30 seconds apart, 2 x 500 mcg, total dose of 1000 mcg) once daily for 84 consecutive days via DISKUS™ device.

Subjects will receive 2 inhalations of placebo once daily for 84 days via DISKUS device.

Subjects will receive 2 inhalations of GSK2269557 700 mcg once daily for 84 consecutive days via ELLIPTA.

Subjects will receive Placebo once daily for 84 consecutive days via ELLIPTA.

Outcomes

Primary Outcome Measures

Change in Messenger Ribonucleic Acid (mRNA) Transcriptome in Induced Sputum After 12, 28 and 84 Days of Treatment (Selected Probe Sets With Fold Change >1.5 or <-1.5 and p<0.05) in NEMI Treatment Group

Saline-induced sputum samples were collected at the indicated time-points to determine the alterations in previously identified immune cell mechanisms specifically related to neutrophil function by identifying the changes in mRNA transcriptome in induced sputum. Baseline was defined as screening visit. The log2 transformed mRNA intensities for each probe set were analyzed in a separate repeated measures model. Back transformed baseline-adjusted ratios and two-sided unadjusted p-values were calculated for each visit as the specified time-point value/baseline value. These ratios were converted to fold change values; if ratio >= 1 then fold change=ratio or if ratio < 1 then fold change = -1/ratio. Data for pre-specified probe sets that meet the criteria fold change >1.5 or <-1.5 and p<0.05 for All NEMI, All Placebo and All NEMI/All Placebo group is presented in outcome measure 1, 2 and 3 respectively. In the categories column we have included time-point, Probe ID and Gene label.

Change in mRNA Transcriptome in Induced Sputum After 12, 28 and 84 Days of Treatment (Selected Probe Sets With Fold Change >1.5 or <-1.5 and p<0.05) in Placebo Treatment Group

Saline-induced sputum samples were collected at the indicated time-points to determine the alterations in previously identified immune cell mechanisms specifically related to neutrophil function by identifying the changes in mRNA transcriptome in induced sputum. Baseline was defined as screening visit. The log2 transformed mRNA intensities for each probe set were analysed in a separate repeated measures model. Back transformed baseline-adjusted ratios and two-sided unadjusted p-values were calculated for each visit as the specified time-point value/baseline value. These ratios were converted to fold change values; if ratio >= 1 then fold change=ratio or if ratio < 1 then fold change = -1/ratio. Data for pre-specified probe sets that meet the criteria fold change >1.5 or <-1.5 and p<0.05 for All NEMI, All Placebo and All NEMI/All Placebo group is presented in outcome measure 1, 2 and 3 respectively. In the categories column we have included time-point, Probe ID and Gene label.

Saline-induced sputum samples were collected at the indicated time-points to determine the alterations in previously identified immune cell mechanisms specifically related to neutrophil function by identifying the changes in mRNA transcriptome in induced sputum. For each probe set, the log2 transformed mRNA intensities were analyzed in separate repeated measures models. The models included a Treatment, Visit and Treatment*Visit term. The Visit consisted of 4 levels: Screening (Baseline), Day 12, Day 28 and Day 84, and the Treatment consisted of three levels: Null (when Visit = Screening), All Placebo and All NEMI. The fold changes were derived from the back transformed ratio from Baselines as fold change = ratio if ratio is >=1, else if ratio <1 then fold change = -1/ratio. Data for pre-specified probe sets that meet the criteria fold change >1.5 and p<0.05 for All NEMI, All Placebo and All NEMI/All Placebo group is presented in outcome measure 1, 2 and 3 respectively.

Secondary Outcome Measures

Change From Baseline in Specific Imaging Airway Volume (siVaw) at Functional Residual Capacity (FRC) and Total Lung Capacity (TLC) for Individual Lobes

siVaw was measured at FRC and TLC. Data was collected at longitudinal time points (Untrimmed data): Baseline (Screening), Day 12 & Day 28 and at each time point for scan trimmed pairs: SCRD12, SCRD28 & D12D28. At each time point it was measure at 5 lobes (right upper lobe, left upper lobe, right middle lobe, right lower lobe & left lower lobe) and 5 Regions (Upper, Lower, Central, Distal & Total). For Untrimmed data and SCRD12 & SCRD28 scan trimmed pairs the baseline is screening, for D12D28 scan trimmed pair the baseline is D12. Change from baseline is the post-Baseline value minus the Baseline value. Only participants available at the specified time point were analyzed (n=X1, X2 in the category title). This table presents the untrimmed data (in rows with categories containing untrimmed), SCRD12 scan trim pair data (in rows with categories containing Scan Trimmed and Day 12) and SCRD28 scan trim pair data (in rows with categories containing Scan Trimmed and Day 28) only.

Change From Baseline (Day 12) in siVaw at FRC and TLC for Individual Lobes at Day 28

siVaw is a measure of the volume in an individual's airway corrected for their lobar volume derived from the high resolution computed tomography (HRCT). It was measured at FRC and TLC. Data was collected at longitudinal time points (Untrimmed data): Baseline (Screening), Day 12 & Day 28 and at each time point for scan trimmed pairs: SCRD12, SCRD28 & D12D28. At each time point it was measure at 5 lobes (right upper lobe, left upper lobe, right middle lobe, right lower lobe & left lower lobe) and 5 Regions (Upper, Lower, Central, Distal & Total). For Untrimmed data and SCRD12 & SCRD28 scan trimmed pairs the baseline is screening, for D12D28 scan trimmed pair the baseline is D12. Change from baseline is the post-Baseline value minus the Baseline value. Only participants available at the specified time point were analyzed (represented by n=X1, X2 in the category title). This table presents the D12D28 scan trim pair data only.

Change From Baseline in siVaw at FRC and TLC for Individual Regions

siVaw was measured at FRC and TLC. Data was collected at longitudinal time points (Untrimmed data): Baseline (Screening), Day 12 & Day 28 and at each time point for scan trimmed pairs: SCRD12, SCRD28 & D12D28. At each time point it was measure at 5 lobes (right upper lobe, left upper lobe, right middle lobe, right lower lobe & left lower lobe) and 5 Regions (Upper, Lower, Central, Distal & Total). For Untrimmed data and SCRD12 & SCRD28 scan trimmed pairs the baseline is screening, for D12D28 scan trimmed pair the baseline is D12. Change from baseline is the post-Baseline value minus the Baseline value. Only participants available at the specified time point were analyzed (n=X1, X2 in the category title).This table presents the untrimmed data (in rows with categories containing untrimmed), SCRD12 scan trim pair data (in rows with categories containing Scan Trimmed and Day 12) and SCRD28 scan trim pair data (in rows with categories containing Scan Trimmed and Day 28) only.

Change From Baseline (Day 12) in siVaw at FRC and TLC for Individual Regions at Day 28

Change From Baseline in Imaging Airway Volume (iVaw) at FRC and TLC for Individual Lobes

iVaw was measured at FRC and TLC. Data was collected at longitudinal time points (Untrimmed data): Screening, Day 12 & Day 28 and at each time point for scan trimmed pairs: SCRD12, SCRD28 & D12D28. At each time point it was measure at 5 lobes (right upper lobe, left upper lobe, right middle lobe, right lower lobe & left lower lobe) and 5 Regions (Upper, Lower, Central, Distal & Total). For Untrimmed data and SCRD12 & SCRD28 scan trimmed pairs the baseline is screening, for D12D28 scan trimmed pair the baseline is D12. Change from baseline is the post-Baseline value minus the Baseline value. Only participants available at the specified time point were analyzed (n=X1, X2 in the category title). This table presents the untrimmed data (in rows with categories containing untrimmed), SCRD12 scan trim pair data (in rows with categories containing Scan Trimmed and Day 12) and SCRD28 scan trim pair data (in rows with categories containing Scan Trimmed and Day 28) only.

Change From Baseline (Day 12) in iVaw at FRC and TLC for Individual Lobes at Day 28

iVaw is a measure of the volume in an individual's airway derived from the HRCT. It was measured at FRC and TLC. Data was collected at longitudinal time points (Untrimmed data): Screening, Day 12 & Day 28 and at each time point for scan trimmed pairs: SCRD12, SCRD28 & D12D28. At each time point it was measure at 5 lobes (right upper lobe, left upper lobe, right middle lobe, right lower lobe & left lower lobe) and 5 Regions (Upper, Lower, Central, Distal & Total). For Untrimmed data and SCRD12 & SCRD28 scan trimmed pairs the baseline is screening, for D12D28 scan trimmed pair the baseline is D12. Change from baseline is the post-Baseline value minus the Baseline value. Only participants available at the specified time point were analyzed (represented by n=X1, X2 in the category title). This table presents the D12D28 scan trim pair data only.

Change From Baseline in iVaw at FRC and TLC for Individual Regions

Change From Baseline (Day 12) in iVaw at FRC and TLC for Individual Regions at Day 28

Change From Baseline in Imaging Airway Resistance (iRaw) at FRC and TLC for Individual Lobes

iRaw is a measure of the resistance in an individual's airway derived from HRCT. It was measured at FRC and TLC. Data was collected at each time point for scan trimmed pairs: SCRD12, SCRD28 & D12D28. At each time point it was measure at 5 lobes (right upper lobe, left upper lobe, right middle lobe, right lower lobe & left lower lobe) and 5 Regions (Upper, Lower, Central, Distal & Total). For SCRD12 & SCRD28 scan trimmed pairs the baseline is screening, for D12D28 scan trimmed pair the baseline is D12. Change from baseline is the post-Baseline value minus the Baseline value. Only participants available at the specified time point were analyzed (represented by n=X1, X2 in the category title). • This table presents the SCRD12 scan trim pair data (in rows with categories containing Scan Trimmed and Day 12) and SCRD28 scan trim pair data (in rows with categories containing Scan Trimmed and Day 28) only.

Change From Baseline (Day 12) in iRaw at FRC and TLC for Individual Lobes at Day 28

iRaw is a measure of the resistance in an individual's airway derived from HRCT. It was measured at FRC and TLC. Data was collected at each time point for scan trimmed pairs: SCRD12, SCRD28 & D12D28. At each time point it was measure at 5 lobes (right upper lobe, left upper lobe, right middle lobe, right lower lobe & left lower lobe) and 5 Regions (Upper, Lower, Central, Distal & Total). For SCRD12 & SCRD28 scan trimmed pairs the baseline is screening, for D12D28 scan trimmed pair the baseline is D12. Change from baseline is the post-Baseline value minus the Baseline value. Only participants available at the specified time point were analyzed (represented by n=X1, X2 in the category title). This table presents the D12D28 scan trim pair data only.

Change From Baseline in iRaw at FRC and TLC for Individual Regions

iRaw is a measure of the resistance in an individual's airway derived from HRCT. It was measured at FRC and TLC. Data was collected at each time point for scan trimmed pairs: SCRD12, SCRD28 & D12D28. At each time point it was measure at 5 lobes (right upper lobe, left upper lobe, right middle lobe, right lower lobe & left lower lobe) and 5 Regions (Upper, Lower, Central, Distal & Total). For SCRD12 & SCRD28 scan trimmed pairs the baseline is screening, for D12D28 scan trimmed pair the baseline is D12. Change from baseline is the post-Baseline value minus the Baseline value. Only participants available at the specified time point were analyzed (n=X1, X2 in the category title). This table presents the SCRD12 scan trim pair data (in rows with categories containing Scan Trimmed and Day 12) and SCRD28 scan trim pair data (in rows with categories containing Scan Trimmed and Day 28) only.

Change From Baseline (Day 12) in iRaw at FRC and TLC for Individual Regions at Day 28

iRaw is a measure of the resistance in an individual's airway derived from HRCT. It was measured at FRC and TLC. Data was collected at each time point for scan trimmed pairs: SCRD12, SCRD28 & D12D28. At each time point it was measure at 5 lobes (right upper lobe, left upper lobe, right middle lobe, right lower lobe & left lower lobe) and 5 Regions (Upper, Lower, Central, Distal & Total). For SCRD12 & SCRD28 scan trimmed pairs the baseline is screening, for D12D28 scan trimmed pair the baseline is D12. Change from baseline is the post-Baseline value minus the Baseline value. Only participants available at the specified time point were analyzed (represented by n=X1, X2 in the category title). This table presents the D12D28 scan trim pair data only.

Change From Baseline in Specific Imaging Airway Resistance (siRaw) at FRC and TLC for Individual Lobes

siRaw is a measure of the resistance in an individual's airway corrected for their lobar volume derived from the HRCT. It was measured at FRC and TLC. Data was collected at each time point for scan trimmed pairs: SCRD12, SCRD28 & D12D28. At each time point it was measure at 5 lobes (right upper lobe, left upper lobe, right middle lobe, right lower lobe & left lower lobe) and 5 Regions (Upper, Lower, Central, Distal & Total). For SCRD12 & SCRD28 scan trimmed pairs the baseline is screening, for D12D28 scan trimmed pair the baseline is D12. Change from baseline is the post-Baseline value minus the Baseline value. Only participants available at the specified time point were analysed (represented by n=X1, X2 in the category title). This table presents the SCRD12 scan trim pair data (in rows with categories containing Scan Trimmed and Day 12) and SCRD28 scan trim pair data (in rows with categories containing Scan Trimmed and Day 28) only.

Change From Baseline (Day 12) in Specific Imaging Airway Resistance (siRaw) at FRC and TLC for Individual Lobes at Day 28

Change From Baseline in Specific Imaging Airway Resistance (siRaw) at FRC and TLC for Individual Regions

Change From Baseline (Day 12) in Specific Imaging Airway Resistance (siRaw) at FRC and TLC for Individual Regions at Day 28

Change From Baseline in Lung Lobar Volume (iVlobe) at FRC and TLC for Individual Lobes

Change from Baseline in lung lobar volumes was measured at FRC and TLC scan conditions. Data was collected at longitudinal time points: Baseline (Screening), Day 12 and Day 28. At each time point it was measure at 5 lobes (right upper lobe, left upper lobe, right middle lobe, right lower lobe & left lower lobe). The value at Screening was considered as Baseline. Change from baseline is the post-Baseline value minus the Baseline value. The study had a protocol amendment to reflect changes in manufacturing device from DISKUS to ELLIPTA after study had been initiated, but the 2 treatment arms remained the same i.e. Placebo and NEMI.There was no intent to compare two devices.

Change From Baseline in Lung Lobar Volume (iVlobe) at FRC and TLC for Individual Regions

Change from Baseline in lung lobar volumes was measured at FRC and TLC scan conditions. Data was collected at longitudinal time points: Baseline (Screening), Day 12 and Day 28. At each time point it was measure at 5 Regions (Upper, Lower, Central, Distal & Total). The value at Screening was considered as Baseline. Change from Baseline is the post-Baseline value minus the Baseline value. The study had a protocol amendment to reflect changes in manufacturing device from DISKUS to ELLIPTA after study had been initiated, but the 2 treatment arms remained the same i.e. Placebo and NEMI.There was no intent to compare two devices.

Change From Baseline in Trachea Length and Diameter at FRC and TLC

Trachea length and diameter was derived from HRCT. It was measured at both FRC and TLC scan conditions. The value at Screening was considered as Baseline. Change from Baseline is the post-Baseline value minus the Baseline value. The change from Baseline data is presented for Day 12 and Day 28 for trachea length and diameter. The study had a protocol amendment to reflect changes in manufacturing device from DISKUS to ELLIPTA after study had been initiated, but the 2 treatment arms remained the same i.e. Placebo and NEMI.There was no intent to compare two devices.

Change From Baseline (Average Day 1 to 3) Peak Expiratory Flow (PEF)

PEF measurements were taken (in triplicate) daily in the morning before dose administration, as soon as it is safe for the participant to do so. The best/highest result was recorded. Participants were provided with a handheld device. Baseline here is defined as average of Day 1 to Day 3. Change from Baseline is the post-Baseline value minus the Baseline value. The study had a protocol amendment to reflect changes in manufacturing device from DISKUS to ELLIPTA after study had been initiated, but the 2 treatment arms remained the same i.e. Placebo and NEMI. There was no intent to compare two devices.

Mean Number of Occasions of Rescue Usage Per Day

For reliever/rescue use, bronchodilator use recorded in the diary was summarized as the mean number of occasions of rescue use per day.where a rescue-free day was defined as a 24-hour period in which the number of occasions of bronchodilator use was zero. Number of occasions bronchodilator taken in the last 24 hours were collected in the daily diary. The mean number of occasions of rescue use per day, were calculated for each participant during the four weekly periods (Weeks 1 to 4; Weeks 5-8 and Weeks 9-12). The study had a protocol amendment to reflect changes in manufacturing device from DISKUS to ELLIPTA after study had been initiated, but the 2 treatment arms remained the same i.e. Placebo and NEMI.There was no intent to compare two devices.

Mean Rescue Medication Free Days

For reliever/rescue use, bronchodilator use recorded in the diary was summarized as the mean number of occasions of rescue use per day, where a rescue-free day was defined as a 24-hour period in which the number of occasions of bronchodilator use was zero. Number of occasions bronchodilator taken in the last 24 hours were collected in the daily diary. The mean number of rescue free days were calculated for each participant during the four weekly periods (Weeks 1 to 4; Weeks 5-8 and Weeks 9-12). The study had a protocol amendment to reflect changes in manufacturing device from DISKUS to ELLIPTA after study had been initiated, but the 2 treatment arms remained the same i.e. Placebo and NEMI. There was no intent to compare two devices.

Change From Baseline in Forced Expiratory Volume in One Second (FEV1) and Forced Vital Capacity (FVC)

FEV1 is the volume of air that can forcibly be blown out in one second. A triplicate FEV1 measurement were taken daily in the morning before dose administration using the site's spirometer as soon as it was safe to do so. FVC is defined as the amount of air that can be forcibly exhaled from the lungs after taking the deepest breath possible. Baseline is the latest available measurement from Day 2 Within 48 hours /discharge (On Treatment) and Day 1 (Pre-Treatment). Change from Baseline is the post-Baseline value minus Baseline value. The study had a protocol amendment to reflect changes in manufacturing device from DISKUS to ELLIPTA after study had been initiated, but the 2 treatment arms remained the same i.e. Placebo and NEMI.There was no intent to compare two devices.

Number of Participants With Worst Case Hematology Results Post-Baseline Relative to Baseline

Blood samples were collected to analyze the following s hematology parameters: Hemoglobin, Hematocrit, Mean Corpuscle Hemoglobin (MCH), Mean Corpuscle Volume (MCV), Platelet count, Red Blood Cell (RBC) count, White Blood Cell (WBC) count, Neutrophils, Lymphocytes, Monocytes, Eosinophils and Basophils. Participants were counted in the worst case category that their value changes to (low or high), unless there is no change in their category. Participants whose lab value category was unchanged (example given [e.g.],High to High), or whose value became normal, were not recorded. Participants were counted twice if the participant had values that changed 'To Low' and 'To High', so the percentages may not add to 100%. The value at Screening was considered as Baseline. Data for Worst Case Laboratory Hematology values Post-Baseline Relative to Baseline has been presented.

Number of Participants With Worst Case Chemistry Results Post-Baseline Relative to Baseline

Blood samples were collected to analyze the following Chemistry parameters: Albumin, Alkaline Phosphatase (ALP), Alanine Amino Transferase (ALT), Aspartate Amino Transferase (AST), Direct Bilirubin, Total Bilirubin, Calcium, C-Reactive protein, Creatinine, Glucose, Potassium, Sodium, Total Protein and Urea/Blood urea nitrogen. Participants were counted in the worst case category that their value changes to (low, normal or high), unless there is no change in their category. Participants whose lab value category was unchanged e.g. High to High), or whose value became normal, were not recorded. Participants were counted twice if the participant had values that changed 'To Low' and 'To High', so the percentages may not add to 100%. The value at Screening was considered as Baseline. Data for Worst Case Laboratory chemistry values Post-Baseline Relative to Baseline has been presented.

Number of Participants With Worst Case Vital Sign Results Relative to Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline

Vital signs were measured in semi-supine position after 5 minutes rest and included Systolic blood pressure (SBP), Diastolic blood pressure (DBP), Heart rate (HR). Data for number of participants with Post-Baseline worst case Vital Sign results relative to PCI Criteria relative to Baseline was presented. PCI ranges were: SBP (lower: <85 and upper: >160 mmHg), DBP (lower: <45 and upper: >100 mmHg), and HR (lower: <40 and upper: >110 bpm). The value at Screening was considered as Baseline.

Number of Participants With Worst Case Post-Baseline Abnormal Electrocardiogram (ECG) Findings

A Single 12-lead ECGs was obtained at screening and at each other timepoint during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QT interval corrected using the Fridericia's formula (QTcF) intervals. Data for number of participants with worst case post-Baseline abnormal ECG findings was reported. The value at Screening was considered as Baseline.

Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)

An AE is any untoward medical occurrence in a clinical investigation 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 medical occurrence that at any dose, resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, is associated with liver injury and impaired liver function or any other situation according to medical or scientific judgment was categorized as SAE. Number of participants with AEs and SAEs have been reported.

Maximum Plasma Concentration (Cmax) Following Administration of NEMI

Blood samples for pharmacokinetic (PK) analysis was collected at the indicated time points following administration of NEMI via DISKUS and ELLIPTA.

Trough Concentration Following Administration of NEMI

Blood samples for pharmacokinetic (PK) analysis was collected at the indicated time points following administration of NEMI via DISKUS and ELLIPTA.

Full Information

NCT ID

NCT02522299

First Posted

August 3, 2015

Last Updated

August 12, 2021

Sponsor

GlaxoSmithKline

1. Study Identification

Unique Protocol Identification Number

NCT02522299

Brief Title

A Study to Evaluate the Safety, Efficacy and Changes in Induced Sputum and Blood Biomarkers Following Daily Repeat Doses of Inhaled GSK2269557 in Chronic Obstructive Pulmonary Disease (COPD) Subjects With Acute Exacerbation

Official Title

A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety, Efficacy and Changes in Induced Sputum and Blood Biomarkers Following Daily Repeat Doses of Inhaled GSK2269557 for 12 Weeks in Adult Subjects Diagnosed With an Acute Exacerbation of Chronic Obstructive Pulmonary Disease (COPD)

Study Type

Interventional

2. Study Status

Record Verification Date

August 2021

Overall Recruitment Status

Completed

Study Start Date

November 4, 2015 (Actual)

Primary Completion Date

June 15, 2018 (Actual)

Study Completion Date

June 22, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

GlaxoSmithKline

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

The purpose of this study is to evaluate specific alterations in immune cell mechanisms related to neutrophil function as detected by PI3Kdelta-dependent changes in messenger ribonucleic acid (mRNA) extracted from induced sputum in patients experiencing an exacerbation of COPD, with or without treatment with GSK2269557. The efficacy of treatment with GSK2269557 will also be measured using functional respiratory imaging (FRI) and spirometry. This is a randomised, double-blind, placebo-controlled, parallel-group study. The study consisted of Screening Phase (up to 3 days prior to Day 1), Treatment Phase (Days 1 to 84) and Follow phase (7 to 14 days after last dose). The total duration of the study is 13-14 weeks including the screening visit. DISKUS TM and ELLIPTA TM are registered trademark of GSK group of companies.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Pulmonary Disease, Chronic Obstructive

Keywords

double-blind, PI3Kdelta, GSK2269557, exacerbation, Chronic Obstructive Pulmonary Disease, randomised, placebo-controlled

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

44 (Actual)

8. Arms, Groups, and Interventions

Arm Title

GSK2269557 1000 microgram (mcg)

Arm Type

Experimental

Arm Description

Subjects will receive 2 inhalations of GSK2269557 (30 seconds apart, 2 x 500 mcg, total dose of 1000 mcg) once daily for 84 consecutive days via DISKUS™ device.

Arm Title

Placebo via DISKUS

Arm Type

Placebo Comparator

Arm Description

Subjects will receive 2 inhalations of placebo once daily for 84 days via DISKUS device.

Arm Title

GSK2269557 700 mcg

Arm Type

Experimental

Arm Description

Subjects will receive 2 inhalations of GSK2269557 700 mcg once daily for 84 consecutive days via ELLIPTA.

Arm Title

Placebo via ELLIPTA

Arm Type

Placebo Comparator

Arm Description

Subjects will receive Placebo once daily for 84 consecutive days via ELLIPTA.

Intervention Type

Drug

Intervention Name(s)

GSK2269557

Intervention Description

GSK2269557 500 mcg blended with lactose per blister and will be administered using a DISKUS dry powder inhaler device. Since GSK2269557 will no longer be manufactured for use with the DISKUS device, it will be replaced with ELLIPTA Device. Subjects will receive GSK2269557 700 mcg once daily for 84 consecutive days via ELLIPTA.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

Lactose will be administered using a DISKUS and ELLIPTA dry powder inhaler device

Intervention Type

Device

Intervention Name(s)

DISKUS

Intervention Description

It is multi-dose dry powder inhaler containing one foil strip of drug with 60 blisters

Intervention Type

Device

Intervention Name(s)

ELLIPTA

Intervention Description

It is multi-dose dry powder inhaler containing one foil strip of drug with 30 blisters

Primary Outcome Measure Information:

Title

Description

Time Frame

Baseline (Screening) and Days 12, 28 and 84

Title

Change in mRNA Transcriptome in Induced Sputum After 12, 28 and 84 Days of Treatment (Selected Probe Sets With Fold Change >1.5 or <-1.5 and p<0.05) in Placebo Treatment Group

Description

Saline-induced sputum samples were collected at the indicated time-points to determine the alterations in previously identified immune cell mechanisms specifically related to neutrophil function by identifying the changes in mRNA transcriptome in induced sputum. Baseline was defined as screening visit. The log2 transformed mRNA intensities for each probe set were analysed in a separate repeated measures model. Back transformed baseline-adjusted ratios and two-sided unadjusted p-values were calculated for each visit as the specified time-point value/baseline value. These ratios were converted to fold change values; if ratio >= 1 then fold change=ratio or if ratio < 1 then fold change = -1/ratio. Data for pre-specified probe sets that meet the criteria fold change >1.5 or <-1.5 and p<0.05 for All NEMI, All Placebo and All NEMI/All Placebo group is presented in outcome measure 1, 2 and 3 respectively. In the categories column we have included time-point, Probe ID and Gene label.

Time Frame

Baseline (Screening) and Days 12, 28 and 84

Title

Description

Saline-induced sputum samples were collected at the indicated time-points to determine the alterations in previously identified immune cell mechanisms specifically related to neutrophil function by identifying the changes in mRNA transcriptome in induced sputum. For each probe set, the log2 transformed mRNA intensities were analyzed in separate repeated measures models. The models included a Treatment, Visit and Treatment*Visit term. The Visit consisted of 4 levels: Screening (Baseline), Day 12, Day 28 and Day 84, and the Treatment consisted of three levels: Null (when Visit = Screening), All Placebo and All NEMI. The fold changes were derived from the back transformed ratio from Baselines as fold change = ratio if ratio is >=1, else if ratio <1 then fold change = -1/ratio. Data for pre-specified probe sets that meet the criteria fold change >1.5 and p<0.05 for All NEMI, All Placebo and All NEMI/All Placebo group is presented in outcome measure 1, 2 and 3 respectively.

Time Frame

Baseline (Screening) and Days 12, 28 and 84

Secondary Outcome Measure Information:

Title

Change From Baseline in Specific Imaging Airway Volume (siVaw) at Functional Residual Capacity (FRC) and Total Lung Capacity (TLC) for Individual Lobes

Description

Time Frame

Baseline (Screening), Days 12 and 28

Title

Change From Baseline (Day 12) in siVaw at FRC and TLC for Individual Lobes at Day 28

Description

Time Frame

Baseline (Day 12) and Day 28

Title

Change From Baseline in siVaw at FRC and TLC for Individual Regions

Description

siVaw was measured at FRC and TLC. Data was collected at longitudinal time points (Untrimmed data): Baseline (Screening), Day 12 & Day 28 and at each time point for scan trimmed pairs: SCRD12, SCRD28 & D12D28. At each time point it was measure at 5 lobes (right upper lobe, left upper lobe, right middle lobe, right lower lobe & left lower lobe) and 5 Regions (Upper, Lower, Central, Distal & Total). For Untrimmed data and SCRD12 & SCRD28 scan trimmed pairs the baseline is screening, for D12D28 scan trimmed pair the baseline is D12. Change from baseline is the post-Baseline value minus the Baseline value. Only participants available at the specified time point were analyzed (n=X1, X2 in the category title).This table presents the untrimmed data (in rows with categories containing untrimmed), SCRD12 scan trim pair data (in rows with categories containing Scan Trimmed and Day 12) and SCRD28 scan trim pair data (in rows with categories containing Scan Trimmed and Day 28) only.

Time Frame

Baseline (Screening), Days 12 and 28

Title

Change From Baseline (Day 12) in siVaw at FRC and TLC for Individual Regions at Day 28

Description

Time Frame

Baseline (Day 12) and Day 28

Title

Change From Baseline in Imaging Airway Volume (iVaw) at FRC and TLC for Individual Lobes

Description

Time Frame

Baseline (Screening) and Days 12 and 28

Title

Change From Baseline (Day 12) in iVaw at FRC and TLC for Individual Lobes at Day 28

Description

Time Frame

Baseline (Day 12) and Day 28

Title

Change From Baseline in iVaw at FRC and TLC for Individual Regions

Description

Time Frame

Baseline (Screening) and Days 12 and 28

Title

Change From Baseline (Day 12) in iVaw at FRC and TLC for Individual Regions at Day 28

Description

Time Frame

Baseline (Day 12) and Day 28

Title

Change From Baseline in Imaging Airway Resistance (iRaw) at FRC and TLC for Individual Lobes

Description

Time Frame

Baseline (Screening) and Days 12 and 28

Title

Change From Baseline (Day 12) in iRaw at FRC and TLC for Individual Lobes at Day 28

Description

iRaw is a measure of the resistance in an individual's airway derived from HRCT. It was measured at FRC and TLC. Data was collected at each time point for scan trimmed pairs: SCRD12, SCRD28 & D12D28. At each time point it was measure at 5 lobes (right upper lobe, left upper lobe, right middle lobe, right lower lobe & left lower lobe) and 5 Regions (Upper, Lower, Central, Distal & Total). For SCRD12 & SCRD28 scan trimmed pairs the baseline is screening, for D12D28 scan trimmed pair the baseline is D12. Change from baseline is the post-Baseline value minus the Baseline value. Only participants available at the specified time point were analyzed (represented by n=X1, X2 in the category title). This table presents the D12D28 scan trim pair data only.

Time Frame

Baseline (Day 12) and Day 28

Title

Change From Baseline in iRaw at FRC and TLC for Individual Regions

Description

iRaw is a measure of the resistance in an individual's airway derived from HRCT. It was measured at FRC and TLC. Data was collected at each time point for scan trimmed pairs: SCRD12, SCRD28 & D12D28. At each time point it was measure at 5 lobes (right upper lobe, left upper lobe, right middle lobe, right lower lobe & left lower lobe) and 5 Regions (Upper, Lower, Central, Distal & Total). For SCRD12 & SCRD28 scan trimmed pairs the baseline is screening, for D12D28 scan trimmed pair the baseline is D12. Change from baseline is the post-Baseline value minus the Baseline value. Only participants available at the specified time point were analyzed (n=X1, X2 in the category title). This table presents the SCRD12 scan trim pair data (in rows with categories containing Scan Trimmed and Day 12) and SCRD28 scan trim pair data (in rows with categories containing Scan Trimmed and Day 28) only.

Time Frame

Baseline (Screening) and Days 12 and 28

Title

Change From Baseline (Day 12) in iRaw at FRC and TLC for Individual Regions at Day 28

Description

iRaw is a measure of the resistance in an individual's airway derived from HRCT. It was measured at FRC and TLC. Data was collected at each time point for scan trimmed pairs: SCRD12, SCRD28 & D12D28. At each time point it was measure at 5 lobes (right upper lobe, left upper lobe, right middle lobe, right lower lobe & left lower lobe) and 5 Regions (Upper, Lower, Central, Distal & Total). For SCRD12 & SCRD28 scan trimmed pairs the baseline is screening, for D12D28 scan trimmed pair the baseline is D12. Change from baseline is the post-Baseline value minus the Baseline value. Only participants available at the specified time point were analyzed (represented by n=X1, X2 in the category title). This table presents the D12D28 scan trim pair data only.

Time Frame

Baseline (Day 12) and Day 28

Title

Change From Baseline in Specific Imaging Airway Resistance (siRaw) at FRC and TLC for Individual Lobes

Description

Time Frame

Baseline (Screening) and Days 12 and 28

Title

Change From Baseline (Day 12) in Specific Imaging Airway Resistance (siRaw) at FRC and TLC for Individual Lobes at Day 28

Description

Time Frame

Baseline (Day 12) and Day 28

Title

Change From Baseline in Specific Imaging Airway Resistance (siRaw) at FRC and TLC for Individual Regions

Description

Time Frame

Baseline (Screening) and Days 12 and 28

Title

Change From Baseline (Day 12) in Specific Imaging Airway Resistance (siRaw) at FRC and TLC for Individual Regions at Day 28

Description

Time Frame

Baseline (Day 12) and Day 28

Title

Change From Baseline in Lung Lobar Volume (iVlobe) at FRC and TLC for Individual Lobes

Description

Time Frame

Baseline (Screening) and Days 12 and 28

Title

Change From Baseline in Lung Lobar Volume (iVlobe) at FRC and TLC for Individual Regions

Description

Change from Baseline in lung lobar volumes was measured at FRC and TLC scan conditions. Data was collected at longitudinal time points: Baseline (Screening), Day 12 and Day 28. At each time point it was measure at 5 Regions (Upper, Lower, Central, Distal & Total). The value at Screening was considered as Baseline. Change from Baseline is the post-Baseline value minus the Baseline value. The study had a protocol amendment to reflect changes in manufacturing device from DISKUS to ELLIPTA after study had been initiated, but the 2 treatment arms remained the same i.e. Placebo and NEMI.There was no intent to compare two devices.

Time Frame

Baseline (Screening) and Days 12 and 28

Title

Change From Baseline in Trachea Length and Diameter at FRC and TLC

Description

Time Frame

Baseline (Screening) and Days 12 and 28

Title

Change From Baseline (Average Day 1 to 3) Peak Expiratory Flow (PEF)

Description

Time Frame

Baseline and up to Day 84

Title

Mean Number of Occasions of Rescue Usage Per Day

Description

Time Frame

Weeks 1 to 4; Weeks 5 to 8 and Weeks 9 to 12

Title

Mean Rescue Medication Free Days

Description

Time Frame

Weeks 1 to 4; Weeks 5 to 8 and Weeks 9 to 12

Title

Change From Baseline in Forced Expiratory Volume in One Second (FEV1) and Forced Vital Capacity (FVC)

Description

Time Frame

Baseline and Days 12, 28, 56, 84

Title

Number of Participants With Worst Case Hematology Results Post-Baseline Relative to Baseline

Description

Time Frame

Baseline (Screening) and up to 14 weeks

Title

Number of Participants With Worst Case Chemistry Results Post-Baseline Relative to Baseline

Description

Time Frame

Baseline (Screening) and up to 14 weeks

Title

Number of Participants With Worst Case Vital Sign Results Relative to Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline

Description

Time Frame

Baseline (Screening) and up to 14 weeks

Title

Number of Participants With Worst Case Post-Baseline Abnormal Electrocardiogram (ECG) Findings

Description

Time Frame

Up to 14 weeks

Title

Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)

Description

Time Frame

Up to 14 weeks

Title

Maximum Plasma Concentration (Cmax) Following Administration of NEMI

Description

Blood samples for pharmacokinetic (PK) analysis was collected at the indicated time points following administration of NEMI via DISKUS and ELLIPTA.

Time Frame

Day 1: 5 minutes Post-dose on Day 1

Title

Trough Concentration Following Administration of NEMI

Description

Blood samples for pharmacokinetic (PK) analysis was collected at the indicated time points following administration of NEMI via DISKUS and ELLIPTA.

Time Frame

Day 1: 24 Hours post-dose; Days 12, 28, 56, 84: Pre-dose

10. Eligibility

Sex

All

Minimum Age & Unit of Time

40 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Between 40 and 80 years of age inclusive, at the time of signing the informed consent. The subject has a confirmed and established diagnosis of COPD, as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines for at least 6 months prior to entry. The subject is able to produce >100 milligram (mg) of sputum at screening for processing, (ie, total weight of sputum plugs). The subject has a post-bronchodilator FEV1/FVC <0.7 and FEV1 <=80 % of predicted. Disease severity: Acute exacerbation of COPD requiring an escalation in therapy to include both corticosteroid and antibiotics. Acute exacerbation to be confirmed by an experienced physician and represent a recent change in at least two major and one minor symptoms, one major and two minor symptoms, or all 3 major symptoms. Major symptoms: Subjective increase in dyspnea; Increase in sputum volume; Change in sputum colour. Minor symptoms: Cough; Wheeze; Sore throat The subject is a smoker or an ex-smoker with a smoking history of at least 10 pack years (pack years = [cigarettes per day smoked/20 x number of years smoked]). Body weight >= 45 kilogram (kg) and body mass index (BMI) within the range 16 to 35 kilogram per meter square (kg/m^2) (inclusive) Male Female subject: is eligible to participate if she is not pregnant (as confirmed by a negative urine human chorionic gonadotrophin [hCG] test), not lactating, and at least one of the following conditions applies: (1)Non-reproductive potential defined as: Pre-menopausal females with one of the following: Documented tubal ligation; Documented hysteroscopic tubal occlusion procedure with follow-up confirmation of bilateral tubal occlusion; Hysterectomy; Documented Bilateral Oophorectomy. Postmenopausal defined as 12 months of spontaneous amenorrhea. Females whose menopausal status is in doubt will be required to use, or have been using, one of the highly effective contraception methods as specified below from 30 days prior to the first dose of study medication and until completion of the follow-up visit. 2)Reproductive potential and agrees to follow one of the options listed below in the GlaxoSmithKline (GSK) Modified List of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential (FRP) requirements from 30 days prior to the first dose of study medication and until completion of the follow-up visit. GSK Modified List of Highly Effective Methods for Avoiding Pregnancy in FRP. This list does not apply to FRP with same sex partners, when this is their preferred and usual lifestyle or for subjects who are and will continue to be abstinent from penile-vaginal intercourse on a long term and persistent basis. 1) Contraceptive subdermal implant that meets GSK standard criteria including a <1% rate of failure per year, as stated in the product label. 2) Intrauterine device or intrauterine system that meets GSK standard criteria including a <1% rate of failure per year, as stated in the product label. 3) Oral Contraceptive, either combined or progestogen alone. 4) Injectable progestogen. 5) Contraceptive vaginal ring. 6) Percutaneous contraceptive patches. 7) Male partner sterilization with documentation of azoospermia prior to the female subject's entry into the study, and this male is the sole partner for that subject. 8) Male condom combined with a vaginal spermicide (foam, gel, film, cream, or suppository). These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception. Specific inclusion criteria for Male subjects with female partners of reproductive potential is outlined below: Male subjects with female partners of child bearing potential must comply with the following contraception requirements from the time of first dose of study medication until after the completion of the follow up visit. 1) Vasectomy with documentation of azoospermia. 2) Male condom plus partner use of one of the contraceptive options below: Contraceptive subdermal implant that meets GSK standard criteria including a <1% rate of failure per year, as stated in the product label. Intrauterine device or intrauterine system that meets GSK standard criteria including a <1% rate of failure per year, as stated in the product label. Oral Contraceptive, either combined or progestogen alone. Injectable progestogen. Contraceptive vaginal ring. Percutaneous contraceptive patches. These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring that subjects understand how to properly use these methods of contraception. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol. Exclusion Criteria: To avoid recruitment of subjects with a severe COPD exacerbation, the presence of any one of the following severity criteria will render the subject ineligible for inclusion in the study: Need for invasive mechanical ventilation (short term [<48 hour] Non-invasive ventilation [NIV] or continuous positive airway pressure [CPAP] is acceptable); Haemodynamic instability or clinically significant heart failure; Confusion; Clinically significant pneumonia, identified by chest X-ray at screening, and as judged by the Investigator. Subjects who have current medical conditions or diseases that are not well controlled and, which as judged by the Investigator, may affect subject safety or influence the outcome of the study. (Note: Patients with adequately treated and well controlled concurrent medical conditions (e.g. hypertension or noninsulin-dependent diabetes mellitus [NIDDM]) are permitted to be entered into the study). Subject has a diagnosis of active tuberculosis, lung cancer, clinically overt bronchiectasis, pulmonary fibrosis, asthma or any other respiratory condition that might, in the opinion of the investigator, compromise the safety of the subject or affect the interpretation of the results. ALT >2xupper limit of normal (ULN) and bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the exclusion criteria, outside of the reference range for the population being studied may be included if the Investigator [in consultation with the GSK Medical Monitor if required] documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures. Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) ECG indicative of an acute cardiac event (e.g. Myocardial Infarction) or demonstrating a clinically significant arrhythmia requiring treatment. QTcF > 450 msec or QTcF > 480 msec in subjects with Bundle Branch Block, based on single QTcF value. Subjects who have undergone lung volume reduction surgery. Subject is currently on chronic treatment with macrolides or long term antibiotics. Subject is being treated with long term oxygen therapy (LTOT) (>15 hours/day). The subject has been on chronic treatment with anti-Tumour Necrosis Factor (anti-TNF), or any other immunosuppressive therapy (except corticosteroid) within 60 days prior to dosing History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >28 units for males or >21 units for females. One unit is equivalent to 8 gram (g) of alcohol: a half-pint (~240 milliliter [mL]) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits. History of sensitivity to any of the study medications, or components thereof (such as lactose) or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation. A known (historical) positive test for human immunodeficiency virus (HIV) antibody. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result at screening or within 3 months prior to first dose of study treatment. NOTE: Because of the short window for screening, treatment with GSK2269557 may start before receiving the result of the hepatitis tests. If subsequently the test is found to be positive, the subject may be withdrawn, as judged by the Principal Investigator in consultation with the Medical Monitor. Where participation in the study would result in donation of blood or blood products in excess of 500 mL within 56 days. 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: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). Exposure to more than 4 investigational medicinal products within 12 months prior to the first dosing day.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

GSK Clinical Trials

Organizational Affiliation

GlaxoSmithKline

Official's Role

Study Director

Facility Information:

Facility Name

GSK Investigational Site

City

Vancouver

State/Province

British Columbia

ZIP/Postal Code

V5Z 1M9

Country

Canada

Facility Name

GSK Investigational Site

City

Hamilton

State/Province

Ontario

ZIP/Postal Code

L8N 3Z5

Country

Canada

Facility Name

GSK Investigational Site

City

Montreal

State/Province

Ontario

ZIP/Postal Code

H4A 3J1

Country

Canada

Facility Name

GSK Investigational Site

City

Montreal

State/Province

Quebec

ZIP/Postal Code

H2W1T8

Country

Canada

Facility Name

GSK Investigational Site

City

Quebec

ZIP/Postal Code

G1V 4G5

Country

Canada

Facility Name

GSK Investigational Site

City

Odense

ZIP/Postal Code

DK-5000

Country

Denmark

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

IPD for this study is available via the Clinical Study Data Request site

IPD Sharing Time Frame

IPD is available via the Clinical Study Data Request site (copy the URL below to your browser)

IPD Sharing 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.

IPD Sharing URL

https://www.clinicalstudydatarequest.com/Posting.aspx?ID=20861

Citations:

PubMed Identifier

34113094

Citation

Begg M, Hamblin JN, Jarvis E, Bradley G, Mark S, Michalovich D, Lennon M, Wajdner HE, Amour A, Wilson R, Saunders K, Tanaka R, Arai S, Tang T, Van Holsbeke C, De Backer J, Vos W, Titlestad IL, FitzGerald JM, Killian K, Bourbeau J, Poirier C, Maltais F, Cahn A, Hessel EM. Exploring PI3Kdelta Molecular Pathways in Stable COPD and Following an Acute Exacerbation, Two Randomized Controlled Trials. Int J Chron Obstruct Pulmon Dis. 2021 Jun 3;16:1621-1636. doi: 10.2147/COPD.S309303. eCollection 2021.

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