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

NCT ID: NCT03250689

Last Updated: 2021-03-29

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 19 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-11-15
• Study Completion Date: 2018-10-08

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.

Conditions

Pulmonary Disease, Chronic Obstructive

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Danirixin 35 mg

Eligible subjects will receive danirixin 35 mg tablet with food twice daily for 14 Days.

Group Type: EXPERIMENTAL

Danirixin

Intervention Type: DRUG

Danirixin will be available as 35 mg oval shaped, white film coated HBr embossed tablets.

Rescue medication

Intervention Type: DRUG

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.

Inhaled COPD maintenance medication

Intervention Type: DRUG

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)

Placebo Comparator

Eligible subjects will receive placebo tablet with food twice daily for 14 Days.

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

Placebo will be available as oval shaped, white film coated tablets.

Rescue medication

Intervention Type: DRUG

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.

Inhaled COPD maintenance medication

Intervention Type: DRUG

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)

Interventions

Danirixin

Danirixin will be available as 35 mg oval shaped, white film coated HBr embossed tablets.

Intervention Type: DRUG

Placebo

Placebo will be available as oval shaped, white film coated tablets.

Intervention Type: DRUG

Rescue medication

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.

Intervention Type: DRUG

Inhaled COPD maintenance medication

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)

Intervention Type: DRUG

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.

• Minimum Eligible Age: 50 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Dundee, , United Kingdom

Countries

United Kingdom

References

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.

Reference Type: BACKGROUND

PMID: 33263062 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2017-001069-25

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

207551

Identifier Type: -

Identifier Source: org_study_id