Randomized Study Evaluating the Effect of Danirixin on Neutrophil Extracellular Traps (NETs) in Chronic Obstructive Pulmonary Disease (COPD)
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Intervention: Danirixin; Placebo; Rescue medication; Inhaled COPD maintenance medication
Intervention description: Danirixin will be available as 35 mg oval shaped, white film coated HBr embossed tablets.; Placebo will be available as oval shaped, white film coated tablets.; 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.; 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)
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 19.0
Sex: All
Minimum age: 50 Years
Maximum age: 75 Years
Healthy volunteers: No
Keywords: Danirixin; CXCR2; NETs; GSK1325756; COPD; HBr

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.