Clinical trial NCT03250689: Randomized Study Evaluating the Effect of Danirixin on Neutrophil Extracellular Traps (NETs) in Chronic Obstructive Pulmonary Disease (COPD)
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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: Danirixin
CXCR2
NETs
GSK1325756
COPD
HBr
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2017-08-16
Enrollment: 19
Sex: ALL
Minimum age (years): 50
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Percentage Change From Baseline in Sputum Neutrophil Extracellular Traps (NETs) Quantified by Histone-Elastase Complexes
timeFrame: Baseline (Day 1), Day 7 and Day 14
Secondary outcomes:
measure: Change From Baseline in Sputum NETs Quantified by Deoxyribonucleic Acid (DNA)-Elastase Complexes
timeFrame: Baseline (Day 1), Day 7 and Day 14
measure: Change From Baseline in Percentage of Microscope Field Area Occupied by Sputum NETs
timeFrame: Baseline (Day 1), Day 7 and Day 14
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to Day 21
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline (Day 1), Day 7 and Day 14
measure: Change From Baseline in Heart Rate
timeFrame: Baseline (Day 1), Day 7 and Day 14
measure: Change From Baseline in Respiration Rate
timeFrame: Baseline (Day 1), Day 7 and Day 14
measure: Change From Baseline in PR Interval, QRS Duration, QT Interval and QT Interval Corrected for Heart Rate According to Fridericia's Formula (QTcF)
timeFrame: Baseline (Day 1) and Day 14
measure: Spirometry: Forced Expiratory Volume in One Second (FEV1) at Indicated Time Points
timeFrame: Day 1 and Day 14
measure: Spirometry: Forced Vital Capacity (FVC) at Indicated Time Points
timeFrame: Day 1 and Day 14
measure: Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets Counts, Total Neutrophils, White Blood Cell (WBC) Count
timeFrame: Baseline (Day 1) and Day 14
measure: Change From Baseline in Hematology Parameter: Hematocrit
timeFrame: Baseline (Day 1) and Day 14
measure: Change From Baseline in Hematology Parameter: Hemoglobin
timeFrame: Baseline (Day 1) and Day 14
measure: Change From Baseline in Hematology Parameter: Mean Corpuscular Volume
timeFrame: Baseline (Day 1) and Day 14
measure: Change From Baseline in Hematology Parameter: Mean Corpuscular Hemoglobin
timeFrame: Baseline (Day 1) and Day 14
measure: Change From Baseline in Hematology Parameter: Red Blood Cell Count
timeFrame: Baseline (Day 1) and Day 14
measure: Change From Baseline in Chemistry Parameters: Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST)
timeFrame: Baseline (Day 1) and Day 14
measure: Change From Baseline in Chemistry Parameters: Calcium, Glucose, Potassium, Sodium, Urea
timeFrame: Baseline (Day 1) and Day 14
measure: Change From Baseline in Chemistry Parameters: Creatinine, Direct Bilirubin, Total Bilirubin
timeFrame: Baseline (Day 1) and Day 14
measure: Change From Baseline in Urinalysis Parameter: Specific Gravity
timeFrame: Baseline (Day 1) and Day 14
measure: Change From Baseline in Urinalysis Parameter: Potential of Hydrogen (pH)
timeFrame: Baseline (Day 1) and Day 14
measure: Change From Baseline in Sputum Resistin Levels
timeFrame: Baseline (Day 1), Day 7 and Day 14
measure: Change From Baseline in the Ratio of Sputum NETs to Sputum Neutrophils
timeFrame: Baseline (Day 1) and Day 14
measure: Change From Baseline in Sputum Elastase Activity
timeFrame: Baseline (Day 1), Day 7 and Day 14
measure: Change From Baseline in Peripheral Blood Neutrophil NETs Formation Quantified by DNA Release
timeFrame: Baseline (Day 1) and Day 14
measure: Percentage Change From Baseline in Peripheral Blood Neutrophil NETs Formation Quantified by Microscopy
timeFrame: Baseline (Day 1) and Day 14
measure: Maximum Observed Concentration (Cmax) of Danirixin
timeFrame: Days 1 and 14: Pre-dose and 0.5, 1, 2 and 4 hours post-dose
measure: Time to Cmax (Tmax) of Danirixin
timeFrame: Days 1 and 14: Pre-dose and 0.5, 1, 2 and 4 hours post-dose
measure: Area Under the Blood Concentration-time Curve [AUC(0-t)] of Danirixin
timeFrame: Days 1 and 14: Pre-dose and 0.5, 1, 2 and 4 hours post-dose
measure: Time of Last Observed Concentration (Tlast) of Danirixin
timeFrame: Days 1 and 14: Pre-dose and 0.5, 1, 2 and 4 hours post-dose
Other outcomes:
Locations:
city: Dundee
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Keir HR, Richardson H, Fillmore C, Shoemark A, Lazaar AL, Miller BE, Tal-Singer R, Chalmers JD, Mohan D. CXCL-8-dependent and -independent neutrophil activation in COPD: experiences from a pilot study of the CXCR2 antagonist danirixin. ERJ Open Res. 2020 Nov 10;6(4):00583-2020. doi: 10.1183/23120541.00583-2020. eCollection 2020 Oct.