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

NCT02522299 | Completed Phase 2 Results

• 2 other identifiers: 2019282015-003696-30
• Study Type: interventional
• Target: 44
• Locations: 2 countries
• Sites: 6

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.

Conditions

Pulmonary Disease, Chronic Obstructive

Keywords

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

Outcome Measures

Primary Outcomes (3)

• 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.

  Baseline (Screening) and Days 12, 28 and 84

• 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.

  Baseline (Screening) and Days 12, 28 and 84

• 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

  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.

  Baseline (Screening) and Days 12, 28 and 84

Secondary Outcomes (30)

• 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

Study Arms (4)

GSK2269557 1000 microgram (mcg)

EXPERIMENTAL

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.

Drug: GSK2269557; Device: DISKUS

Placebo via DISKUS

PLACEBO COMPARATOR

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

Drug: Placebo; Device: DISKUS

GSK2269557 700 mcg

EXPERIMENTAL

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

Device: ELLIPTA

Placebo via ELLIPTA

PLACEBO COMPARATOR

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

Drug: Placebo; Device: ELLIPTA

Interventions

GSK2269557 DRUG

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.

GSK2269557 1000 microgram (mcg)

Placebo DRUG

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

Placebo via DISKUS; Placebo via ELLIPTA

DISKUS DEVICE

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

GSK2269557 1000 microgram (mcg); Placebo via DISKUS

ELLIPTA DEVICE

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

GSK2269557 700 mcg; Placebo via ELLIPTA

Eligibility Criteria

• Age: 40 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the consent form and in this protocol.

You may not qualify if:

• 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%).
• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (6)

GSK Investigational Site

Vancouver, British Columbia, V5Z 1M9, Canada

Location

GSK Investigational Site

Hamilton, Ontario, L8N 3Z5, Canada

Location

GSK Investigational Site

Montreal, Ontario, H4A 3J1, Canada

Location

GSK Investigational Site

Montreal, Quebec, H2W1T8, Canada

Location

GSK Investigational Site

Québec, Quebec, G1V 4G5, Canada

Location

GSK Investigational Site

Odense, DK-5000, Denmark

Location

Related Publications (1)

• 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.

  PMID: 34113094 BACKGROUND

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Interventions

Nemiralisib

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: GSK Response Center
• Organization: GlaxoSmithKline

GSKClinicalSupportHD@gsk.com

866-435-7343

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 3, 2015
• First Posted: August 13, 2015
• Study Start: November 4, 2015
• Primary Completion: June 15, 2018
• Study Completion: June 22, 2018
• Last Updated: September 5, 2021
• Results First Posted: November 25, 2019

Record last verified: 2021-08

Data Sharing

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

Locations

CA (5); DK (1)