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

NCT03250689 | Terminated Phase 2 Results

• 2 other identifiers: 2075512017-001069-25
• Study Type: interventional
• Target: 19
• Locations: 1 country
• Sites: 1

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

Keywords

Danirixin; CXCR2; NETs; GSK1325756; COPD; HBr

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (29)

• Change From Baseline in Sputum NETs Quantified by Deoxyribonucleic Acid (DNA)-Elastase Complexes

  Baseline (Day 1), Day 7 and Day 14

• Change From Baseline in Percentage of Microscope Field Area Occupied by Sputum NETs

  Baseline (Day 1), Day 7 and Day 14

• Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

  Up to Day 21

• Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)

  Baseline (Day 1), Day 7 and Day 14

• Change From Baseline in Heart Rate

  Baseline (Day 1), Day 7 and Day 14

Study Arms (2)

Danirixin 35 mg

EXPERIMENTAL

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

Drug: Danirixin; Drug: Rescue medication; Drug: Inhaled COPD maintenance medication

Placebo Comparator

EXPERIMENTAL

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

Drug: Placebo; Drug: Rescue medication; Drug: Inhaled COPD maintenance medication

Interventions

Danirixin DRUG

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

Danirixin 35 mg

Placebo DRUG

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

Placebo Comparator

Rescue medication 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.

Danirixin 35 mg; Placebo Comparator

Inhaled COPD maintenance medication 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)

Danirixin 35 mg; Placebo Comparator

Eligibility Criteria

• Age: 50 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Dundee, DD1 9SY, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 33263062 BACKGROUND

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Interventions

danirixin

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 11, 2017
• First Posted: August 16, 2017
• Study Start: November 15, 2017
• Primary Completion: October 8, 2018
• Study Completion: October 8, 2018
• Last Updated: March 29, 2021
• Results First Posted: November 8, 2019

Record last verified: 2021-02

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

GB (1)