Pulmonary Disease, Chronic ObstructivePhase 2NCT03250689
Randomized Study Evaluating the Effect of Danirixin on Neutrophil Extracellular Traps (NETs) in Chronic Obstructive Pulmonary Disease (COPD)
A Phase 2 study testing Danirixin, Rescue medication and Inhaled COPD maintenance medication in people with Pulmonary Disease, Chronic Obstructive, run by GlaxoSmithKline at 1 site in United Kingdom.
Trial 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… Read more about this study
- Who is it for?
- Ages 50 to 75 years
- Conditions the study is for
- Pulmonary Disease, Chronic Obstructive
- What is being tested?
- Danirixin, Rescue medication and Inhaled COPD maintenance medication
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 19 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 15 Nov 2017to 8 Oct 2018
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 50 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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).
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- 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.
Who cannot join
- 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.
Show all 25Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
About this 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)
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
- Being tested
- Danirixin, Placebo, Rescue medication, Inhaled COPD maintenance medication
- Keywords
- Danirixin, CXCR2, NETs, GSK1325756, COPD, HBr
- Medical subject headings
- Pulmonary Disease, Chronic Obstructive
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DanirixinDrug
Danirixin will be available as 35 mg oval shaped, white film coated HBr embossed tablets.
PlaceboDrug
Placebo will be available as oval shaped, white film coated tablets.
Rescue medicationDrug
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 medicationDrug
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)
| Study group | Role | What they receive |
|---|---|---|
| Danirixin 35 mg | Experimental | Eligible subjects will receive danirixin 35 mg tablet with food twice daily for 14 Days. Receives: 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. Receives: Drug: Placebo; Drug: Rescue medication; Drug: Inhaled COPD maintenance medication |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: Baseline (Day 1), Day 7 and Day 14
Secondary outcomes (29)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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.
Measured: 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).
Measured: 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.
Measured: Days 1 and 14: Pre-dose and 0.5, 1, 2 and 4 hours post-dose
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Aug 2017
- Study start15 Nov 2017
- Primary completion8 Oct 2018
- Study completion8 Oct 2018
Why it stopped: Study terminated due to a change in the benefit-risk profile for danirixin in COPD.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Pulmonary Disease, Chronic ObstructiveStudies of the same condition, open and under way.
- More trials run by GlaxoSmithKlineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 19 participants (actual)
Sponsor and investigators
- Lead sponsor
- GlaxoSmithKline
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- GSK Clinical Trials, Study director, GlaxoSmithKline
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03250689
- Sponsor's protocol ID
- 207551
- Other IDs
- 2017-001069-25, 2017
- Status last verified
- Feb 2021
- First submitted
- 11 Aug 2017
- Last updated
- 29 Mar 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: IPD for this study is available via the Clinical Study Data Request site.
Publications
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.
PubMed 33263062
Study at a glance
From the registry record, last updated by the sponsor on 29 Mar 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT03250689
- Acronym / sponsor ID
- 207551
- Conditions
- Pulmonary Disease, Chronic Obstructive
- Keywords
- Danirixin, CXCR2, NETs, GSK1325756, COPD, HBr
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Study terminated due to a change in the benefit-risk profile for danirixin in COPD.
- Enrolment
- 19 participants (actual)
- Lead sponsor
- GlaxoSmithKlineIndustry (pharma, biotech, devices)
- Study start
- 15 Nov 2017 (actual)
- Primary completion
- 8 Oct 2018 (actual)
- Study completion
- 8 Oct 2018 (actual)
- First posted
- 16 Aug 2017 (actual)
- Results
- Posted 8 Nov 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Danirixin 35 mg | Experimental | Drug: Danirixin, Drug: Rescue medication, Drug: Inhaled COPD maintenance medicationEligible subjects will receive danirixin 35 mg tablet with food twice daily for 14 Days. |
| Placebo Comparator | Experimental | Drug: Placebo, Drug: Rescue medication, Drug: Inhaled COPD maintenance medicationEligible subjects will receive placebo tablet with food twice daily for 14 Days. |
Who may qualify
- Ages
- 50 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- 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.
Key exclusion criteria (25 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DanirixinDanirixin will be available as 35 mg oval shaped, white film coated HBr embossed tablets. | Drug | Danirixin 35 mg |
| PlaceboPlacebo will be available as oval shaped, white film coated tablets. | Drug | Placebo Comparator |
| Rescue medicationSubjects 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. | Drug | Danirixin 35 mg, Placebo Comparator |
| Inhaled COPD maintenance medicationSubjects 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) | Drug | Danirixin 35 mg, Placebo Comparator |
Primary outcome
Percentage Change From Baseline in Sputum Neutrophil Extracellular Traps (NETs) Quantified by Histone-Elastase Complexes
Time frame: Baseline (Day 1), Day 7 and Day 14
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).
29 secondary outcomes
Change From Baseline in Sputum NETs Quantified by Deoxyribonucleic Acid (DNA)-Elastase Complexes
Time frame: Baseline (Day 1), Day 7 and Day 14
Change From Baseline in Percentage of Microscope Field Area Occupied by Sputum NETs
Time frame: Baseline (Day 1), Day 7 and Day 14
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: Up to Day 21
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
Time frame: Baseline (Day 1), Day 7 and Day 14
Change From Baseline in Heart Rate
Time frame: Baseline (Day 1), Day 7 and Day 14
Change From Baseline in Respiration Rate
Time frame: 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)
Time frame: Baseline (Day 1) and Day 14
Spirometry: Forced Expiratory Volume in One Second (FEV1) at Indicated Time Points
Time frame: Day 1 and Day 14
Spirometry: Forced Vital Capacity (FVC) at Indicated Time Points
Time frame: Day 1 and Day 14
Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets Counts, Total Neutrophils, White Blood Cell (WBC) Count
Time frame: Baseline (Day 1) and Day 14
Change From Baseline in Hematology Parameter: Hematocrit
Time frame: Baseline (Day 1) and Day 14
Change From Baseline in Hematology Parameter: Hemoglobin
Time frame: Baseline (Day 1) and Day 14
Change From Baseline in Hematology Parameter: Mean Corpuscular Volume
Time frame: Baseline (Day 1) and Day 14
Change From Baseline in Hematology Parameter: Mean Corpuscular Hemoglobin
Time frame: Baseline (Day 1) and Day 14
Change From Baseline in Hematology Parameter: Red Blood Cell Count
Time frame: Baseline (Day 1) and Day 14
Change From Baseline in Chemistry Parameters: Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST)
Time frame: Baseline (Day 1) and Day 14
Change From Baseline in Chemistry Parameters: Calcium, Glucose, Potassium, Sodium, Urea
Time frame: Baseline (Day 1) and Day 14
Change From Baseline in Chemistry Parameters: Creatinine, Direct Bilirubin, Total Bilirubin
Time frame: Baseline (Day 1) and Day 14
Change From Baseline in Urinalysis Parameter: Specific Gravity
Time frame: Baseline (Day 1) and Day 14
Change From Baseline in Urinalysis Parameter: Potential of Hydrogen (pH)
Time frame: Baseline (Day 1) and Day 14
Change From Baseline in Sputum Resistin Levels
Time frame: Baseline (Day 1), Day 7 and Day 14
Change From Baseline in the Ratio of Sputum NETs to Sputum Neutrophils
Time frame: Baseline (Day 1) and Day 14
Change From Baseline in Sputum Elastase Activity
Time frame: Baseline (Day 1), Day 7 and Day 14
Change From Baseline in Peripheral Blood Neutrophil NETs Formation Quantified by DNA Release
Time frame: Baseline (Day 1) and Day 14
Percentage Change From Baseline in Peripheral Blood Neutrophil NETs Formation Quantified by Microscopy
Time frame: Baseline (Day 1) and Day 14
Maximum Observed Concentration (Cmax) of Danirixin
Time frame: Days 1 and 14: Pre-dose and 0.5, 1, 2 and 4 hours post-dose
Time to Cmax (Tmax) of Danirixin
Time frame: 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
Time frame: Days 1 and 14: Pre-dose and 0.5, 1, 2 and 4 hours post-dose
Time of Last Observed Concentration (Tlast) of Danirixin
Time frame: Days 1 and 14: Pre-dose and 0.5, 1, 2 and 4 hours post-dose
Results and safety
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Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Mar 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 33263062Keir 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.
- Individual participant dataSharing planned: Yes. IPD for this study is available via the Clinical Study Data Request site.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
GSK Clinical Trials study director
GlaxoSmithKline
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Danirixin, Rescue medication and Inhaled COPD maintenance medication in people with Pulmonary Disease, Chronic Obstructive, run by GlaxoSmithKline at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 29 Mar 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 8 Nov 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage Change From Baseline in Sputum Neutrophil Extracellular Traps (NETs) Quantified by Histone-Elastase Complexes (time frame: Baseline (Day 1), Day 7 and Day 14). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03250689, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Mar 2021.