Clinical trial NCT02522299: 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
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: double-blind
PI3Kdelta
GSK2269557
exacerbation
Chronic Obstructive Pulmonary Disease
randomised
placebo-controlled
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2015-08-13
Enrollment: 44
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: 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
timeFrame: Baseline (Screening) and Days 12, 28 and 84
measure: 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
timeFrame: Baseline (Screening) and Days 12, 28 and 84
measure: 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 All NEMI/All Placebo Comparison Treatment Group
timeFrame: Baseline (Screening) and Days 12, 28 and 84
Secondary outcomes:
measure: Change From Baseline in Specific Imaging Airway Volume (siVaw) at Functional Residual Capacity (FRC) and Total Lung Capacity (TLC) for Individual Lobes
timeFrame: Baseline (Screening), Days 12 and 28
measure: Change From Baseline (Day 12) in siVaw at FRC and TLC for Individual Lobes at Day 28
timeFrame: Baseline (Day 12) and Day 28
measure: Change From Baseline in siVaw at FRC and TLC for Individual Regions
timeFrame: Baseline (Screening), Days 12 and 28
measure: Change From Baseline (Day 12) in siVaw at FRC and TLC for Individual Regions at Day 28
timeFrame: Baseline (Day 12) and Day 28
measure: Change From Baseline in Imaging Airway Volume (iVaw) at FRC and TLC for Individual Lobes
timeFrame: Baseline (Screening) and Days 12 and 28
measure: Change From Baseline (Day 12) in iVaw at FRC and TLC for Individual Lobes at Day 28
timeFrame: Baseline (Day 12) and Day 28
measure: Change From Baseline in iVaw at FRC and TLC for Individual Regions
timeFrame: Baseline (Screening) and Days 12 and 28
measure: Change From Baseline (Day 12) in iVaw at FRC and TLC for Individual Regions at Day 28
timeFrame: Baseline (Day 12) and Day 28
measure: Change From Baseline in Imaging Airway Resistance (iRaw) at FRC and TLC for Individual Lobes
timeFrame: Baseline (Screening) and Days 12 and 28
measure: Change From Baseline (Day 12) in iRaw at FRC and TLC for Individual Lobes at Day 28
timeFrame: Baseline (Day 12) and Day 28
measure: Change From Baseline in iRaw at FRC and TLC for Individual Regions
timeFrame: Baseline (Screening) and Days 12 and 28
measure: Change From Baseline (Day 12) in iRaw at FRC and TLC for Individual Regions at Day 28
timeFrame: Baseline (Day 12) and Day 28
measure: Change From Baseline in Specific Imaging Airway Resistance (siRaw) at FRC and TLC for Individual Lobes
timeFrame: Baseline (Screening) and Days 12 and 28
measure: Change From Baseline (Day 12) in Specific Imaging Airway Resistance (siRaw) at FRC and TLC for Individual Lobes at Day 28
timeFrame: Baseline (Day 12) and Day 28
measure: Change From Baseline in Specific Imaging Airway Resistance (siRaw) at FRC and TLC for Individual Regions
timeFrame: Baseline (Screening) and Days 12 and 28
measure: Change From Baseline (Day 12) in Specific Imaging Airway Resistance (siRaw) at FRC and TLC for Individual Regions at Day 28
timeFrame: Baseline (Day 12) and Day 28
measure: Change From Baseline in Lung Lobar Volume (iVlobe) at FRC and TLC for Individual Lobes
timeFrame: Baseline (Screening) and Days 12 and 28
measure: Change From Baseline in Lung Lobar Volume (iVlobe) at FRC and TLC for Individual Regions
timeFrame: Baseline (Screening) and Days 12 and 28
measure: Change From Baseline in Trachea Length and Diameter at FRC and TLC
timeFrame: Baseline (Screening) and Days 12 and 28
measure: Change From Baseline (Average Day 1 to 3) Peak Expiratory Flow (PEF)
timeFrame: Baseline and up to Day 84
measure: Mean Number of Occasions of Rescue Usage Per Day
timeFrame: Weeks 1 to 4; Weeks 5 to 8 and Weeks 9 to 12
measure: Mean Rescue Medication Free Days
timeFrame: Weeks 1 to 4; Weeks 5 to 8 and Weeks 9 to 12
measure: Change From Baseline in Forced Expiratory Volume in One Second (FEV1) and Forced Vital Capacity (FVC)
timeFrame: Baseline and Days 12, 28, 56, 84
measure: Number of Participants With Worst Case Hematology Results Post-Baseline Relative to Baseline
timeFrame: Baseline (Screening) and up to 14 weeks
measure: Number of Participants With Worst Case Chemistry Results Post-Baseline Relative to Baseline
timeFrame: Baseline (Screening) and up to 14 weeks
measure: Number of Participants With Worst Case Vital Sign Results Relative to Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline
timeFrame: Baseline (Screening) and up to 14 weeks
measure: Number of Participants With Worst Case Post-Baseline Abnormal Electrocardiogram (ECG) Findings
timeFrame: Up to 14 weeks
measure: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
timeFrame: Up to 14 weeks
measure: Maximum Plasma Concentration (Cmax) Following Administration of NEMI
timeFrame: Day 1: 5 minutes Post-dose on Day 1
measure: Trough Concentration Following Administration of NEMI
timeFrame: Day 1: 24 Hours post-dose; Days 12, 28, 56, 84: Pre-dose
Other outcomes:
Locations:
city: Vancouver
country: Canada
facility: GSK Investigational Site
state: British Columbia
city: Hamilton
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Quebec
country: Canada
facility: GSK Investigational Site
city: Odense
country: Denmark
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
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.