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)
Overview
- Phase
- Phase 2
- Intervention
- GSK2269557
- Conditions
- Pulmonary Disease, Chronic Obstructive
- Sponsor
- GlaxoSmithKline
- Enrollment
- 44
- Locations
- 1
- Primary Endpoint
- 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
- Status
- Completed
- Last Updated
- 4 years ago
Overview
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.
Investigators
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)
- •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.
Arms & Interventions
GSK2269557 1000 microgram (mcg)
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.
Intervention: GSK2269557
GSK2269557 1000 microgram (mcg)
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.
Intervention: DISKUS
Placebo via DISKUS
Subjects will receive 2 inhalations of placebo once daily for 84 days via DISKUS device.
Intervention: Placebo
Placebo via DISKUS
Subjects will receive 2 inhalations of placebo once daily for 84 days via DISKUS device.
Intervention: DISKUS
GSK2269557 700 mcg
Subjects will receive 2 inhalations of GSK2269557 700 mcg once daily for 84 consecutive days via ELLIPTA.
Intervention: ELLIPTA
Placebo via ELLIPTA
Subjects will receive Placebo once daily for 84 consecutive days via ELLIPTA.
Intervention: Placebo
Placebo via ELLIPTA
Subjects will receive Placebo once daily for 84 consecutive days via ELLIPTA.
Intervention: ELLIPTA
Outcomes
Primary Outcomes
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
Time Frame: Baseline (Screening) and Days 12, 28 and 84
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.
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
Time Frame: Baseline (Screening) and Days 12, 28 and 84
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 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
Time Frame: Baseline (Screening) and Days 12, 28 and 84
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 Outcomes
- Change From Baseline in Trachea Length and Diameter at FRC and TLC(Baseline (Screening) and Days 12 and 28)
- Change From Baseline (Average Day 1 to 3) Peak Expiratory Flow (PEF)(Baseline and up to Day 84)
- Trough Concentration Following Administration of NEMI(Day 1: 24 Hours post-dose; Days 12, 28, 56, 84: Pre-dose)
- Mean Number of Occasions of Rescue Usage Per Day(Weeks 1 to 4; Weeks 5 to 8 and Weeks 9 to 12)
- Mean Rescue Medication Free Days(Weeks 1 to 4; Weeks 5 to 8 and Weeks 9 to 12)
- Change From Baseline in Specific Imaging Airway Volume (siVaw) at Functional Residual Capacity (FRC) and Total Lung Capacity (TLC) for Individual Lobes(Baseline (Screening), Days 12 and 28)
- Change From Baseline (Day 12) in siVaw at FRC and TLC for Individual Lobes at Day 28(Baseline (Day 12) and Day 28)
- Change From Baseline in siVaw at FRC and TLC for Individual Regions(Baseline (Screening), Days 12 and 28)
- Change From Baseline (Day 12) in siVaw at FRC and TLC for Individual Regions at Day 28(Baseline (Day 12) and Day 28)
- Change From Baseline in Imaging Airway Volume (iVaw) at FRC and TLC for Individual Lobes(Baseline (Screening) and Days 12 and 28)
- Change From Baseline (Day 12) in iVaw at FRC and TLC for Individual Lobes at Day 28(Baseline (Day 12) and Day 28)
- Change From Baseline in iVaw at FRC and TLC for Individual Regions(Baseline (Screening) and Days 12 and 28)
- Change From Baseline in Forced Expiratory Volume in One Second (FEV1) and Forced Vital Capacity (FVC)(Baseline and Days 12, 28, 56, 84)
- Number of Participants With Worst Case Hematology Results Post-Baseline Relative to Baseline(Baseline (Screening) and up to 14 weeks)
- Change From Baseline (Day 12) in iVaw at FRC and TLC for Individual Regions at Day 28(Baseline (Day 12) and Day 28)
- Change From Baseline in Imaging Airway Resistance (iRaw) at FRC and TLC for Individual Lobes(Baseline (Screening) and Days 12 and 28)
- Change From Baseline (Day 12) in iRaw at FRC and TLC for Individual Lobes at Day 28(Baseline (Day 12) and Day 28)
- Change From Baseline (Day 12) in Specific Imaging Airway Resistance (siRaw) at FRC and TLC for Individual Lobes at Day 28(Baseline (Day 12) and Day 28)
- Number of Participants With Worst Case Chemistry Results Post-Baseline Relative to Baseline(Baseline (Screening) and up to 14 weeks)
- Number of Participants With Worst Case Vital Sign Results Relative to Potential Clinical Importance (PCI) Criteria Post-Baseline Relative to Baseline(Baseline (Screening) and up to 14 weeks)
- Change From Baseline in iRaw at FRC and TLC for Individual Regions(Baseline (Screening) and Days 12 and 28)
- Change From Baseline (Day 12) in iRaw at FRC and TLC for Individual Regions at Day 28(Baseline (Day 12) and Day 28)
- Change From Baseline in Specific Imaging Airway Resistance (siRaw) at FRC and TLC for Individual Lobes(Baseline (Screening) and Days 12 and 28)
- Change From Baseline in Specific Imaging Airway Resistance (siRaw) at FRC and TLC for Individual Regions(Baseline (Screening) and Days 12 and 28)
- Change From Baseline (Day 12) in Specific Imaging Airway Resistance (siRaw) at FRC and TLC for Individual Regions at Day 28(Baseline (Day 12) and Day 28)
- Change From Baseline in Lung Lobar Volume (iVlobe) at FRC and TLC for Individual Lobes(Baseline (Screening) and Days 12 and 28)
- Change From Baseline in Lung Lobar Volume (iVlobe) at FRC and TLC for Individual Regions(Baseline (Screening) and Days 12 and 28)
- Number of Participants With Worst Case Post-Baseline Abnormal Electrocardiogram (ECG) Findings(Up to 14 weeks)
- Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)(Up to 14 weeks)
- Maximum Plasma Concentration (Cmax) Following Administration of NEMI(Day 1: 5 minutes Post-dose on Day 1)