Randomized Study Evaluating the Effect of Danirixin on Neutrophil Extracellular Traps (NETs) in Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
=================
Brief Summary
-----------------
The inflammation associated with COPD is characterized by a prominent infiltration of neutrophils in lung tissue and airways. The CXC chemokine receptor type 2 (CXCR2) plays a pivotal role in neutrophil recruitment to the lungs resulting in progressive fibrosis, airway stenosis, and destruction of the lung parenchyma characteristic of COPD. There is a paucity of novel therapies that target these symptoms, and there are no currently available therapies that modify disease progression in COPD. Danirixin (GSK1325756) is a selective CXCR2 antagonist being developed as a potential anti-inflammatory agent for the treatment of COPD and influenza. This study is a mechanistic study which aims to evaluate the effect of danirixin in reducing neutrophil extracellular traps (NETs) formation (or NETosis). Subjects will be randomized (3:1) to receive danirixin hydrobromide (HBr) 35 milligram (mg) orally twice daily or matching placebo for 14 days. Subjects may continue to use rescue medication(s) and inhaled COPD maintenance medication(s) during the study. The study will consist of a screening period of up to 30 days, a 2 week treatment period, and a 1-week follow-up visit via phone call. Approximately 50 subjects will be screened to obtain approximately 24 subjects to complete the study.

Official Title
-----------------
Randomized Double Blind (Sponsor Unblind) Study Evaluating the Effect of 14 Days of Treatment With Danirixin (GSK1325756) on Neutrophil Extracellular Traps (NETs) Formation in Participants With Stable Chronic Obstructive Pulmonary Disease (COPD)

Conditions
-----------------
Pulmonary Disease, Chronic Obstructive

Intervention / Treatment
-----------------
* Drug: Danirixin
* Drug: Placebo
* Drug: Rescue medication
* Drug: Inhaled COPD maintenance medication


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject must be 50 to 75 years of age inclusive, at the time of signing the informed consent. Diagnosis of COPD with mild to moderate airflow obstruction FEV1/FVC ratio <0.7 and FEV1% predicted (pred) >=40% at screening) based on the Quanjer reference equations, with spirometry conducted according to American Thoracic Society (ATS)/European Respiratory Society (ERS) current guidelines. Elevated sputum neutrophil extracellular traps based on screening assay for histone-elastase complexes of >0.5 units/ milliliter (mL) sputum. Two further screening samples can be submitted for analysis within 30 day screening period if previous samples do not pass criteria. Able to produce at least 1 mL of sputum sample at the screening visit with nebulized saline induction. Current smokers and former smokers with a cigarette smoking history of >=10 pack years (1 pack year=20 cigarettes smoked per day for 1 year or equivalent). Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1. Body weight >=45 kilogram (kg). Male or female. A male subject must agree to use contraception during the treatment period and for at least [60 hours, corresponding to approximately 6 half-lives (which is the time needed to eliminate any teratogenic treatments after the last dose of study treatment and refrain from donating sperm during this period. A female subject is eligible to participate if she is not pregnant, not breastfeeding, and is not a woman of childbearing potential (WOCBP) OR a WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 60 hours after the last dose of study treatment. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Exclusion Criteria: Primary clinical diagnoses of any of the following relevant lung diseases; asthma, sarcoidosis, tuberculosis, pulmonary fibrosis, severe bronchiectasis or lung cancer. Known alpha-1-antitrypsin deficiency. Pulse oximetry <88% at rest at screening. Subjects should be tested while breathing room air. Subjects on long term oxygen therapy (defined as >15 hours/day of oxygen use). Unstable co-morbidities (e.g. cardiovascular disease, active malignancy) which in the opinion of the Investigator would make the subject unsuitable to be enrolled in the study. This includes any abnormality identified on screening bloods or screening ECG which in the opinion of the Investigator would make the subject unsuitable for the study. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator of GSK medical monitor, contraindicates their participation. Current or chronic history of liver disease, or know hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years. Antibiotic use concurrently or within 28 days preceding the screening visit, including current or planned chronic use of macrolide antibiotics during the study period for the prevention of COPD exacerbations. Examples of chronic use include daily or two-three times per week for at least 3 months. Systemic immunosuppressive medication, including current oral corticosteroids at a dose >5 milligram (mg), concurrently or within 28 days preceding the screening visit. Oral or injectable Cytochrome P450 (CYP) 3A4 or Breast Cancer Resistance Protein (BCRP) substrates with narrow therapeutic index (CYP3A4 substrates include, but are not limited to, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, and theophylline; BCRP substrates include: Methotrexate, mitoxantrone, imatinib, irinotecan, lapatinib, rosuvastatin, sulfasalazine, topotecan. Current use of phosphodiesterase-4 inhibitors: Roflumilast, Crisaborole and Apremilast. Current use of Raloxifene. Current use of low molecular weight heparin. 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 four investigational products within 12 months prior to the first dosing day. Subjects with a peripheral blood neutrophil count < 1.0x10^9/liter (L) at screening. Diagnosis of pneumonia (chest X-ray or computed tomography [CT] confirmed) within the 3 months prior to screening. Chest X-ray (posterior with lateral) or CT scan reveals evidence of a clinically significant abnormality not believed to be due to the presence of COPD (historic data up to 1 year may be used). Abnormal and clinically significant 12-lead ECG finding at screening. The investigator will determine the clinical significance of each abnormal ECG finding in relation to the subject's medical history and exclude subjects who would be at undue risk by participating in the trial. An abnormal and clinically significant finding that would preclude a subject from entering the trial is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the following: AF with rapid ventricular rate > 120 beats per minute (bpm); Sustained or non-sustained ventricular tachycardia (VT); Second degree heart block Mobitz type II and third degree heart block (unless pacemaker or defibrillator has been implanted); QT interval corrected for heart rate by Fridericia's formula (QTcF) >=500 millisecond (msec) in subjects with QRS <120 msec and QTcF >=530 msec in subjects with QRS >=120 msec. Affiliation with a study site: study investigators, sub-investigators, study coordinators, employees of a study investigator, sub-investigator or study site, or immediate family members of any of the above that is involved with the study.

Ages Eligible for Study
-----------------
Minimum Age: 50 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Danirixin 35 mg<br>Eligible subjects will receive danirixin 35 mg tablet with food twice daily for 14 Days. | Drug: Danirixin<br>* Danirixin will be available as 35 mg oval shaped, white film coated HBr embossed tablets.<br>Drug: Rescue medication<br>* Subjects may continue to use rescue medication(s) anytime during the study. The following rescue medications may be used: short acting beta agonists, short acting muscarinic antagonists, or short acting combination bronchodilators.<br>Drug: Inhaled COPD maintenance medication<br>* Subjects may continue to use inhaled COPD maintenance medication(s) during the study, at the discretion of the GSK Medical Monitor and/or Investigator. The following maintenance medications may be used: long acting bronchodilator medications (e.g. long-acting muscarinic antagonist [LAMA], long-acting beta-agonist [LABA]) and long-acting bronchodilator combination therapies (e.g. LAMA/LABA) and long-acting bronchodilator/inhaled corticosteroid steroid combination (ICS) therapies (e.g. LABA/ICS, LAMA/LABA/ICS)<br>|
| Experimental: Placebo Comparator<br>Eligible subjects will receive placebo tablet with food twice daily for 14 Days. | Drug: Placebo<br>* Placebo will be available as oval shaped, white film coated tablets.<br>Drug: Rescue medication<br>* Subjects may continue to use rescue medication(s) anytime during the study. The following rescue medications may be used: short acting beta agonists, short acting muscarinic antagonists, or short acting combination bronchodilators.<br>Drug: Inhaled COPD maintenance medication<br>* Subjects may continue to use inhaled COPD maintenance medication(s) during the study, at the discretion of the GSK Medical Monitor and/or Investigator. The following maintenance medications may be used: long acting bronchodilator medications (e.g. long-acting muscarinic antagonist [LAMA], long-acting beta-agonist [LABA]) and long-acting bronchodilator combination therapies (e.g. LAMA/LABA) and long-acting bronchodilator/inhaled corticosteroid steroid combination (ICS) therapies (e.g. LABA/ICS, LAMA/LABA/ICS)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change From Baseline in Sputum Neutrophil Extracellular Traps (NETs) Quantified by Histone-Elastase Complexes | Sputum samples were collected at indicated time points to assess NET formation via histone elastase complexes. Baseline was considered as Day 1. If Day 1 values were missing, screening value was imputed for Baseline. Change from Baseline was calculated as post-Baseline value minus Baseline value. Percentage change from Baseline was calculated by dividing change from Baseline value by Baseline value and multiplied by 100. Analysis was performed using a mixed effect repeated measures model with covariates of treatment group, log(Baseline NETs) and treatment group by day interaction. The response variable was the log of the ratio of post-Baseline NETs to Baseline NETs. Primary completer population consisted of all participants in the Modified Intent-To-Treat population who had completed the assessments supporting the primary endpoint (sputum NETs). | Baseline (Day 1), Day 7 and Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Sputum NETs Quantified by Deoxyribonucleic Acid (DNA)-Elastase Complexes | Sputum samples were collected at indicated time points to assess NET formation via DNA elastase complexes. Baseline was considered as Day 1. If Day 1 values were missing, screening value was imputed for Baseline. Change from Baseline was calculated as post-Baseline value minus Baseline value. | Baseline (Day 1), Day 7 and Day 14 | 
| Change From Baseline in Percentage of Microscope Field Area Occupied by Sputum NETs | Sputum samples were collected at indicated time points and NETs area was quantified by microscopy. Baseline was considered as Day 1. If Day 1 values were missing, screening value was imputed for Baseline. Change from Baseline was calculated as post-Baseline value minus Baseline value. | Baseline (Day 1), Day 7 and Day 14 | 
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. A SAE is defined as any untoward medical occurrence that, at any dose results in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes, Modified Intent-to-Treat Population consisted of all randomized participants who received at least one dose of study treatment. | Up to Day 21 | 
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP and DBP were measured in seated position after 5 minutes rest for the participants at indicated time points. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value. | Baseline (Day 1), Day 7 and Day 14 | 
| Change From Baseline in Heart Rate | Heart rate was measured in seated position after 5 minutes rest for the participants at indicated time points. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value. | Baseline (Day 1), Day 7 and Day 14 | 
| Change From Baseline in Respiration Rate | Respiration rate was measured in seated position after 5 minutes rest for the participants at indicated time points. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value. | Baseline (Day 1), Day 7 and Day 14 | 
| Change From Baseline in PR Interval, QRS Duration, QT Interval and QT Interval Corrected for Heart Rate According to Fridericia's Formula (QTcF) | Triplicate 12-lead electrocardiograms (ECG) were obtained to measure PR Interval, QRS Duration, QT Interval and QTcF Interval. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value. | Baseline (Day 1) and Day 14 | 
| Spirometry: Forced Expiratory Volume in One Second (FEV1) at Indicated Time Points | FEV1 is the amount of air that can be forcefully exhaled from the lungs in the first second of a forced exhalation. It was measured by spirometry test. Mean and standard deviation data of FEV1 measured at Day 1 and Day 14 have been presented. | Day 1 and Day 14 | 
| Spirometry: Forced Vital Capacity (FVC) at Indicated Time Points | FVC is defined as the amount of air that can be forcibly exhaled from the lungs after taking the deepest breath possible. It was measured by spirometry test. Mean and standard deviation data of FVC measured at Day 1 and Day 14 have been presented. | Day 1 and Day 14 | 
| Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets Counts, Total Neutrophils, White Blood Cell (WBC) Count | Blood samples were collected to analyze the hematology parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets counts, Total neutrophils and WBC count. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value. | Baseline (Day 1) and Day 14 | 
| Change From Baseline in Hematology Parameter: Hematocrit | Blood samples were collected to analyze the hematology parameter: Hematocrit. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value. | Baseline (Day 1) and Day 14 | 
| Change From Baseline in Hematology Parameter: Hemoglobin | Blood samples were collected to analyze the hematology parameter: Hemoglobin. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value. | Baseline (Day 1) and Day 14 | 
| Change From Baseline in Hematology Parameter: Mean Corpuscular Volume | Blood samples were collected to analyze the hematology parameter: Mean Corpuscular Volume. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value. | Baseline (Day 1) and Day 14 | 
| Change From Baseline in Hematology Parameter: Mean Corpuscular Hemoglobin | Blood samples were collected to analyze the hematology parameter: Mean Corpuscular Hemoglobin. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value. | Baseline (Day 1) and Day 14 | 
| Change From Baseline in Hematology Parameter: Red Blood Cell Count | Blood samples were collected to analyze the hematology parameter: Red Blood Cell count. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value. | Baseline (Day 1) and Day 14 | 
| Change From Baseline in Chemistry Parameters: Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST) | Blood samples were collected to analyze the chemistry parameters: ALT, ALP and AST. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value. | Baseline (Day 1) and Day 14 | 
| Change From Baseline in Chemistry Parameters: Calcium, Glucose, Potassium, Sodium, Urea | Blood samples were collected to analyze the chemistry parameters: Calcium, Glucose, Potassium, Sodium and Urea. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value. | Baseline (Day 1) and Day 14 | 
| Change From Baseline in Chemistry Parameters: Creatinine, Direct Bilirubin, Total Bilirubin | Blood samples were collected to analyze the chemistry parameters: Creatinine, Direct Bilirubin and Total Bilirubin. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value. | Baseline (Day 1) and Day 14 | 
| Change From Baseline in Urinalysis Parameter: Specific Gravity | Urinary specific gravity measurement is a part of routine urinalysis. Urine specific gravity is a measure of the concentration of solutes in the urine. It measures the ratio of urine density compared with water density and provides information on the kidney's ability to concentrate urine. The concentration of the excreted molecules determines the urine's specific gravity. Urine samples were collected from participants at indicated time points for analysis of specific gravity. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value. | Baseline (Day 1) and Day 14 | 
| Change From Baseline in Urinalysis Parameter: Potential of Hydrogen (pH) | Urine samples were collected from participants at indicated time points for analysis of pH. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value. | Baseline (Day 1) and Day 14 | 
| Change From Baseline in Sputum Resistin Levels | Sputum samples were collected at indicated time points to analyze resistin levels. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value. | Baseline (Day 1), Day 7 and Day 14 | 
| Change From Baseline in the Ratio of Sputum NETs to Sputum Neutrophils | Sputum samples were collected to calculate ratio of sputum NETs to sputum neutrophils. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value. The ratio is calculated as the sputum NETs divided by the number of sputum neutrophils. | Baseline (Day 1) and Day 14 | 
| Change From Baseline in Sputum Elastase Activity | Sputum samples were collected at indicated time points to analyze sputum elastase activity. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value. | Baseline (Day 1), Day 7 and Day 14 | 
| Change From Baseline in Peripheral Blood Neutrophil NETs Formation Quantified by DNA Release | Blood samples were collected at indicated time points to analyze peripheral blood neutrophil NETs formation by DNA release. DNA-elastase complexes quantified NETs formation. Phorbol 12-myristate 13-acetate (PMA) was used to induce inflammation and NETs formation in the PMA stimulated samples. Blood from participants were tested at Baseline and Day 14 for non-PMA stimulated samples, and at Baseline and Day 14 in PMA-stimulated samples to test whether treatment had any effect on NETs formation either naturally (non PMA induced) or where NETs formation was already raised (PMA stimulated). Hence participants were counted in both the categories - PMA stimulated and not PMA stimulated. NETs formation in peripheral blood was measured with SYTOX green fluorescence quantification of extracellular DNA. Baseline was considered as Day 1. Change from Baseline was calculated as post-Baseline value minus Baseline value. | Baseline (Day 1) and Day 14 | 
| Percentage Change From Baseline in Peripheral Blood Neutrophil NETs Formation Quantified by Microscopy | Blood samples were collected at indicated time points to analyze peripheral blood neutrophil NETs formation by microscopy.DNA-elastase complexes quantified NETs formation.PMA was used to induce inflammation and NETs formation in PMA stimulated samples. Blood from participants were tested at Baseline and Day14 for non-PMA stimulated samples,and at Baseline and Day14 in PMA-stimulated samples to test whether treatment had any effect on NETs formation either naturally(non PMA induced)or where NETs formation was already raised(PMA stimulated).Participants were counted in both categories-PMA stimulated and not PMA stimulated.NETs formation in peripheral blood was measured with SYTOX green fluorescence quantification of extracellular DNA.Baseline was considered as Day1.Change from Baseline was calculated as post-Baseline value minus Baseline value.Percentage change from Baseline was calculated by dividing change from Baseline value by Baseline value and multiplied by100. | Baseline (Day 1) and Day 14 | 
| Maximum Observed Concentration (Cmax) of Danirixin | Blood samples were collected to evaluate the pharmacokinetic (PK) of danirixin at the indicated time points for the analysis of Cmax. PK population consisted of all participants in the Modified Intent-To-Treat population who had at least 1 non-missing PK assessment (non-quantifiable values were considered as non-missing values). | Days 1 and 14: Pre-dose and 0.5, 1, 2 and 4 hours post-dose | 
| Time to Cmax (Tmax) of Danirixin | Blood samples were collected to evaluate the PK of danirixin at the indicated time points for the analysis of Tmax. | Days 1 and 14: Pre-dose and 0.5, 1, 2 and 4 hours post-dose | 
| Area Under the Blood Concentration-time Curve [AUC(0-t)] of Danirixin | Blood samples were collected to evaluate the PK of danirixin at the indicated time points for the analysis of AUC(0-t). | Days 1 and 14: Pre-dose and 0.5, 1, 2 and 4 hours post-dose | 
| Time of Last Observed Concentration (Tlast) of Danirixin | Blood samples were collected to evaluate the PK of danirixin at the indicated time points for the analysis of Tlast. | Days 1 and 14: Pre-dose and 0.5, 1, 2 and 4 hours post-dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Danirixin, CXCR2, NETs, GSK1325756, COPD, HBr