Pulmonary Disease, Chronic Obstructive
Conditions
Keywords
Danirixin, CXCR2, NETs, GSK1325756, COPD, HBr
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.
Interventions
DRUGDanirixin
Danirixin will be available as 35 mg oval shaped, white film coated HBr embossed tablets.
DRUGPlacebo
Placebo will be available as oval shaped, white film coated tablets.
DRUGRescue 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.
DRUGInhaled 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)
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline in Sputum Neutrophil Extracellular Traps (NETs) Quantified by Histone-Elastase Complexes | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Sputum NETs Quantified by Deoxyribonucleic Acid (DNA)-Elastase Complexes | Baseline (Day 1), Day 7 and Day 14 | 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. |
| Change From Baseline in Percentage of Microscope Field Area Occupied by Sputum NETs | Baseline (Day 1), Day 7 and Day 14 | 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. |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Up to Day 21 | 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. |
| Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | Baseline (Day 1), Day 7 and Day 14 | 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. |
| Change From Baseline in Respiration Rate | Baseline (Day 1), Day 7 and Day 14 | 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. |
| Change From Baseline in PR Interval, QRS Duration, QT Interval and QT Interval Corrected for Heart Rate According to Fridericia's Formula (QTcF) | Baseline (Day 1) and Day 14 | 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. |
| Spirometry: Forced Expiratory Volume in One Second (FEV1) at Indicated Time Points | Day 1 and Day 14 | 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. |
| Spirometry: Forced Vital Capacity (FVC) at Indicated Time Points | Day 1 and Day 14 | 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. |
| Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets Counts, Total Neutrophils, White Blood Cell (WBC) Count | Baseline (Day 1) and Day 14 | 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. |
| Change From Baseline in Hematology Parameter: Hematocrit | Baseline (Day 1) and Day 14 | 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. |
| Change From Baseline in Hematology Parameter: Hemoglobin | Baseline (Day 1) and Day 14 | 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. |
| Change From Baseline in Hematology Parameter: Mean Corpuscular Volume | Baseline (Day 1) and Day 14 | 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. |
| Change From Baseline in Hematology Parameter: Mean Corpuscular Hemoglobin | Baseline (Day 1) and Day 14 | 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. |
| Change From Baseline in Hematology Parameter: Red Blood Cell Count | Baseline (Day 1) and Day 14 | 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. |
| Change From Baseline in Heart Rate | Baseline (Day 1), Day 7 and Day 14 | 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. |
| Change From Baseline in Chemistry Parameters: Calcium, Glucose, Potassium, Sodium, Urea | Baseline (Day 1) and Day 14 | 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. |
| Change From Baseline in Chemistry Parameters: Creatinine, Direct Bilirubin, Total Bilirubin | Baseline (Day 1) and Day 14 | 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. |
| Change From Baseline in Urinalysis Parameter: Specific Gravity | Baseline (Day 1) and Day 14 | 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. |
| Change From Baseline in Urinalysis Parameter: Potential of Hydrogen (pH) | Baseline (Day 1) and Day 14 | 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. |
| Change From Baseline in Sputum Resistin Levels | Baseline (Day 1), Day 7 and Day 14 | 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. |
| Change From Baseline in the Ratio of Sputum NETs to Sputum Neutrophils | Baseline (Day 1) and Day 14 | 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. |
| Change From Baseline in Sputum Elastase Activity | Baseline (Day 1), Day 7 and Day 14 | 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. |
| Change From Baseline in Peripheral Blood Neutrophil NETs Formation Quantified by DNA Release | Baseline (Day 1) and Day 14 | 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. |
| Percentage Change From Baseline in Peripheral Blood Neutrophil NETs Formation Quantified by Microscopy | Baseline (Day 1) and Day 14 | 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. |
| Maximum Observed Concentration (Cmax) of Danirixin | Days 1 and 14: Pre-dose and 0.5, 1, 2 and 4 hours post-dose | 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). |
| Time to Cmax (Tmax) of Danirixin | Days 1 and 14: Pre-dose and 0.5, 1, 2 and 4 hours post-dose | Blood samples were collected to evaluate the PK of danirixin at the indicated time points for the analysis of Tmax. |
| Area Under the Blood Concentration-time Curve [AUC(0-t)] of Danirixin | Days 1 and 14: Pre-dose and 0.5, 1, 2 and 4 hours post-dose | Blood samples were collected to evaluate the PK of danirixin at the indicated time points for the analysis of AUC(0-t). |
| Time of Last Observed Concentration (Tlast) of Danirixin | Days 1 and 14: Pre-dose and 0.5, 1, 2 and 4 hours post-dose | Blood samples were collected to evaluate the PK of danirixin at the indicated time points for the analysis of Tlast. |
| Change From Baseline in Chemistry Parameters: Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST) | Baseline (Day 1) and Day 14 | 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. |
Countries
United Kingdom
Participant flow
Recruitment details
The study was conducted at single center in United Kingdom. This study was terminated early due to a change in the benefit risk profile of danirixin observed in another study NCT03034967, leading to cessation of the overall danirixin development program.
Pre-assignment details
A total of 43 participants were screened, of which 23 were screen failures (23 participants did not meet inclusion/exclusion criteria). From the 20 participants who passed screening, 1 was not randomized due to study being terminated early. Hence, 19 participants were enrolled and received treatment in this study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received one tablet of matching placebo twice daily orally with food for 14 days. | 5 |
| Danirixin Hydrobromide 35 mg Participants received one tablet of danirixin hydrobromide 35 milligram (mg) twice daily orally with food for 14 days. | 14 |
| Total | 19 |
Baseline characteristics
| Characteristic | Placebo | Danirixin Hydrobromide 35 mg | Total |
|---|---|---|---|
| Age, Continuous | 61.6 Years STANDARD_DEVIATION 6.02 | 65.3 Years STANDARD_DEVIATION 7.03 | 64.3 Years STANDARD_DEVIATION 6.82 |
| Race/Ethnicity, Customized White: White/Caucasian/European Heritage | 5 Participants | 14 Participants | 19 Participants |
| Sex: Female, Male Female | 2 Participants | 6 Participants | 8 Participants |
| Sex: Female, Male Male | 3 Participants | 8 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 14 |
| other Total, other adverse events | 3 / 5 | 6 / 14 |
| serious Total, serious adverse events | 0 / 5 | 0 / 14 |
Outcome results
Primary
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).
Time frame: Baseline (Day 1), Day 7 and Day 14
Population: Primary Completer Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo | Percentage Change From Baseline in Sputum Neutrophil Extracellular Traps (NETs) Quantified by Histone-Elastase Complexes | Day 7, n=3,6 | -3.2 Percent change |
| Placebo | Percentage Change From Baseline in Sputum Neutrophil Extracellular Traps (NETs) Quantified by Histone-Elastase Complexes | Day 14, n=3,8 | -30.5 Percent change |
| Danirixin Hydrobromide 35 mg | Percentage Change From Baseline in Sputum Neutrophil Extracellular Traps (NETs) Quantified by Histone-Elastase Complexes | Day 7, n=3,6 | -9.4 Percent change |
| Danirixin Hydrobromide 35 mg | Percentage Change From Baseline in Sputum Neutrophil Extracellular Traps (NETs) Quantified by Histone-Elastase Complexes | Day 14, n=3,8 | -13.6 Percent change |
Secondary
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).
Time frame: Days 1 and 14: Pre-dose and 0.5, 1, 2 and 4 hours post-dose
Population: PK Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Area Under the Blood Concentration-time Curve [AUC(0-t)] of Danirixin | Day 1 | 2173.4 Hours * nanograms per milliliter | Geometric Coefficient of Variation 39.57 |
| Placebo | Area Under the Blood Concentration-time Curve [AUC(0-t)] of Danirixin | Day 14 | 2751.1 Hours * nanograms per milliliter | Geometric Coefficient of Variation 51.24 |
Secondary
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.
Time frame: Baseline (Day 1) and Day 14
Population: Modified Intent-to-Treat Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Chemistry Parameters: Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST) | ALT | -1.6 International units per liter | Standard Deviation 4.39 |
| Placebo | Change From Baseline in Chemistry Parameters: Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST) | ALP | 2.8 International units per liter | Standard Deviation 6.26 |
| Placebo | Change From Baseline in Chemistry Parameters: Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST) | AST | -0.6 International units per liter | Standard Deviation 2.61 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Chemistry Parameters: Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST) | ALT | -1.9 International units per liter | Standard Deviation 8.24 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Chemistry Parameters: Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST) | ALP | 1.3 International units per liter | Standard Deviation 13.89 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Chemistry Parameters: Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALP), Aspartate Aminotransferase (AST) | AST | -3.1 International units per liter | Standard Deviation 2.11 |
Secondary
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.
Time frame: Baseline (Day 1) and Day 14
Population: Modified Intent-to-Treat Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Chemistry Parameters: Calcium, Glucose, Potassium, Sodium, Urea | Glucose | 0.36 Millimoles per liter | Standard Deviation 0.635 |
| Placebo | Change From Baseline in Chemistry Parameters: Calcium, Glucose, Potassium, Sodium, Urea | Sodium | 0.0 Millimoles per liter | Standard Deviation 1.58 |
| Placebo | Change From Baseline in Chemistry Parameters: Calcium, Glucose, Potassium, Sodium, Urea | Potassium | -0.12 Millimoles per liter | Standard Deviation 0.148 |
| Placebo | Change From Baseline in Chemistry Parameters: Calcium, Glucose, Potassium, Sodium, Urea | Urea | -0.42 Millimoles per liter | Standard Deviation 0.867 |
| Placebo | Change From Baseline in Chemistry Parameters: Calcium, Glucose, Potassium, Sodium, Urea | Calcium | -0.032 Millimoles per liter | Standard Deviation 0.0782 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Chemistry Parameters: Calcium, Glucose, Potassium, Sodium, Urea | Urea | 0.26 Millimoles per liter | Standard Deviation 0.777 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Chemistry Parameters: Calcium, Glucose, Potassium, Sodium, Urea | Calcium | -0.034 Millimoles per liter | Standard Deviation 0.0947 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Chemistry Parameters: Calcium, Glucose, Potassium, Sodium, Urea | Glucose | 0.12 Millimoles per liter | Standard Deviation 0.398 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Chemistry Parameters: Calcium, Glucose, Potassium, Sodium, Urea | Potassium | 0.06 Millimoles per liter | Standard Deviation 0.287 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Chemistry Parameters: Calcium, Glucose, Potassium, Sodium, Urea | Sodium | 0.2 Millimoles per liter | Standard Deviation 2.04 |
Secondary
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.
Time frame: Baseline (Day 1) and Day 14
Population: Modified Intent-to-Treat Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Chemistry Parameters: Creatinine, Direct Bilirubin, Total Bilirubin | Creatinine | 2.6 Micromoles per liter | Standard Deviation 5.86 |
| Placebo | Change From Baseline in Chemistry Parameters: Creatinine, Direct Bilirubin, Total Bilirubin | Direct Bilirubin | -0.4 Micromoles per liter | Standard Deviation 0.55 |
| Placebo | Change From Baseline in Chemistry Parameters: Creatinine, Direct Bilirubin, Total Bilirubin | Total Bilirubin | 0.8 Micromoles per liter | Standard Deviation 0.84 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Chemistry Parameters: Creatinine, Direct Bilirubin, Total Bilirubin | Direct Bilirubin | 0.7 Micromoles per liter | Standard Deviation 1.65 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Chemistry Parameters: Creatinine, Direct Bilirubin, Total Bilirubin | Creatinine | 1.2 Micromoles per liter | Standard Deviation 6.99 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Chemistry Parameters: Creatinine, Direct Bilirubin, Total Bilirubin | Total Bilirubin | -1.2 Micromoles per liter | Standard Deviation 3.26 |
Secondary
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.
Time frame: Baseline (Day 1), Day 7 and Day 14
Population: Modified Intent-to-Treat Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Heart Rate | Day 7 | 6.8 Beats per minute | Standard Deviation 6.02 |
| Placebo | Change From Baseline in Heart Rate | Day 14 | 4.0 Beats per minute | Standard Deviation 6.89 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Heart Rate | Day 7 | 1.6 Beats per minute | Standard Deviation 11.28 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Heart Rate | Day 14 | 0.1 Beats per minute | Standard Deviation 6.86 |
Secondary
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.
Time frame: Baseline (Day 1) and Day 14
Population: Modified Intent-to-Treat Population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Hematology Parameter: Hematocrit | -0.0058 Percentage of red blood cells in blood | Standard Deviation 0.02279 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Hematology Parameter: Hematocrit | -0.0115 Percentage of red blood cells in blood | Standard Deviation 0.02085 |
Secondary
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.
Time frame: Baseline (Day 1) and Day 14
Population: Modified Intent-to-Treat Population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Hematology Parameter: Hemoglobin | -2.2 Grams per liter | Standard Deviation 6.72 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Hematology Parameter: Hemoglobin | -5.4 Grams per liter | Standard Deviation 7.99 |
Secondary
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.
Time frame: Baseline (Day 1) and Day 14
Population: Modified Intent-to-Treat Population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Hematology Parameter: Mean Corpuscular Hemoglobin | -0.08 Picograms | Standard Deviation 0.92 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Hematology Parameter: Mean Corpuscular Hemoglobin | -0.22 Picograms | Standard Deviation 0.749 |
Secondary
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.
Time frame: Baseline (Day 1) and Day 14
Population: Modified Intent-to-Treat Population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Hematology Parameter: Mean Corpuscular Volume | 0.06 Femtoliter | Standard Deviation 1.339 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Hematology Parameter: Mean Corpuscular Volume | 0.31 Femtoliter | Standard Deviation 1.263 |
Secondary
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.
Time frame: Baseline (Day 1) and Day 14
Population: Modified Intent-to-Treat Population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Hematology Parameter: Red Blood Cell Count | -0.070 Trillion cells per liter | Standard Deviation 0.2081 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Hematology Parameter: Red Blood Cell Count | -0.154 Trillion cells per liter | Standard Deviation 0.2171 |
Secondary
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.
Time frame: Baseline (Day 1) and Day 14
Population: Modified Intent-to-Treat Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets Counts, Total Neutrophils, White Blood Cell (WBC) Count | Lymphocytes | -0.20 Giga cells per liter | Standard Deviation 0.316 |
| Placebo | Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets Counts, Total Neutrophils, White Blood Cell (WBC) Count | Platelets counts | 8.2 Giga cells per liter | Standard Deviation 18.94 |
| Placebo | Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets Counts, Total Neutrophils, White Blood Cell (WBC) Count | Eosinophils | 0.040 Giga cells per liter | Standard Deviation 0.0686 |
| Placebo | Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets Counts, Total Neutrophils, White Blood Cell (WBC) Count | Total neutrophils | -0.38 Giga cells per liter | Standard Deviation 0.965 |
| Placebo | Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets Counts, Total Neutrophils, White Blood Cell (WBC) Count | Monocytes | -0.04 Giga cells per liter | Standard Deviation 0.114 |
| Placebo | Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets Counts, Total Neutrophils, White Blood Cell (WBC) Count | WBC count | -0.56 Giga cells per liter | Standard Deviation 0.948 |
| Placebo | Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets Counts, Total Neutrophils, White Blood Cell (WBC) Count | Basophils | 0.00 Giga cells per liter | Standard Deviation 0 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets Counts, Total Neutrophils, White Blood Cell (WBC) Count | WBC count | 0.16 Giga cells per liter | Standard Deviation 1.075 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets Counts, Total Neutrophils, White Blood Cell (WBC) Count | Basophils | -0.02 Giga cells per liter | Standard Deviation 0.058 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets Counts, Total Neutrophils, White Blood Cell (WBC) Count | Eosinophils | -0.020 Giga cells per liter | Standard Deviation 0.0609 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets Counts, Total Neutrophils, White Blood Cell (WBC) Count | Lymphocytes | -0.08 Giga cells per liter | Standard Deviation 0.269 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets Counts, Total Neutrophils, White Blood Cell (WBC) Count | Monocytes | 0.02 Giga cells per liter | Standard Deviation 0.08 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets Counts, Total Neutrophils, White Blood Cell (WBC) Count | Platelets counts | -7.9 Giga cells per liter | Standard Deviation 41.66 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Hematology Parameters: Basophils, Eosinophils, Lymphocytes, Monocytes, Platelets Counts, Total Neutrophils, White Blood Cell (WBC) Count | Total neutrophils | 0.29 Giga cells per liter | Standard Deviation 0.943 |
Secondary
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.
Time frame: Baseline (Day 1), Day 7 and Day 14
Population: Primary Completer Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Percentage of Microscope Field Area Occupied by Sputum NETs | Day 7 | NA Percentage of microscope field area | — |
| Placebo | Change From Baseline in Percentage of Microscope Field Area Occupied by Sputum NETs | Day 14 | 0.900 Percentage of microscope field area | Standard Error 0.92 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Percentage of Microscope Field Area Occupied by Sputum NETs | Day 7 | NA Percentage of microscope field area | — |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Percentage of Microscope Field Area Occupied by Sputum NETs | Day 14 | -0.259 Percentage of microscope field area | Standard Error 0.5183 |
Secondary
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.
Time frame: Baseline (Day 1) and Day 14
Population: Modified Intent-to-Treat Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Peripheral Blood Neutrophil NETs Formation Quantified by DNA Release | Not PMA stimulated | 3044.8 Relative fluorescence units | Standard Error 4251.78 |
| Placebo | Change From Baseline in Peripheral Blood Neutrophil NETs Formation Quantified by DNA Release | PMA stimulated | -96.8 Relative fluorescence units | Standard Error 9418.43 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Peripheral Blood Neutrophil NETs Formation Quantified by DNA Release | Not PMA stimulated | -721.1 Relative fluorescence units | Standard Error 731.82 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Peripheral Blood Neutrophil NETs Formation Quantified by DNA Release | PMA stimulated | -1211.0 Relative fluorescence units | Standard Error 5102.21 |
Secondary
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.
Time frame: Baseline (Day 1) and Day 14
Population: Modified Intent-to-Treat Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in PR Interval, QRS Duration, QT Interval and QT Interval Corrected for Heart Rate According to Fridericia's Formula (QTcF) | PR Interval | 7.6 Milliseconds | Standard Deviation 20.44 |
| Placebo | Change From Baseline in PR Interval, QRS Duration, QT Interval and QT Interval Corrected for Heart Rate According to Fridericia's Formula (QTcF) | QRS Duration | -0.3 Milliseconds | Standard Deviation 1.12 |
| Placebo | Change From Baseline in PR Interval, QRS Duration, QT Interval and QT Interval Corrected for Heart Rate According to Fridericia's Formula (QTcF) | QT Interval | -4.8 Milliseconds | Standard Deviation 10.05 |
| Placebo | Change From Baseline in PR Interval, QRS Duration, QT Interval and QT Interval Corrected for Heart Rate According to Fridericia's Formula (QTcF) | QTcF Interval | -4.6 Milliseconds | Standard Deviation 0.38 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in PR Interval, QRS Duration, QT Interval and QT Interval Corrected for Heart Rate According to Fridericia's Formula (QTcF) | QTcF Interval | -1.6 Milliseconds | Standard Deviation 5.96 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in PR Interval, QRS Duration, QT Interval and QT Interval Corrected for Heart Rate According to Fridericia's Formula (QTcF) | PR Interval | -4.8 Milliseconds | Standard Deviation 15.69 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in PR Interval, QRS Duration, QT Interval and QT Interval Corrected for Heart Rate According to Fridericia's Formula (QTcF) | QT Interval | 3.7 Milliseconds | Standard Deviation 15.67 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in PR Interval, QRS Duration, QT Interval and QT Interval Corrected for Heart Rate According to Fridericia's Formula (QTcF) | QRS Duration | 0.5 Milliseconds | Standard Deviation 5.55 |
Secondary
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.
Time frame: Baseline (Day 1), Day 7 and Day 14
Population: Modified Intent-to-Treat Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Respiration Rate | Day 7 | -0.6 Breaths per minute | Standard Deviation 1.95 |
| Placebo | Change From Baseline in Respiration Rate | Day 14 | 0.2 Breaths per minute | Standard Deviation 0.84 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Respiration Rate | Day 7 | 1.8 Breaths per minute | Standard Deviation 2.67 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Respiration Rate | Day 14 | 2.1 Breaths per minute | Standard Deviation 3.43 |
Secondary
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.
Time frame: Baseline (Day 1), Day 7 and Day 14
Population: Primary Completer Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Sputum Elastase Activity | Day 7, n=3,6 | 638.0 Nanograms per milliliter | Standard Error 381.36 |
| Placebo | Change From Baseline in Sputum Elastase Activity | Day 14, n=3,8 | 411.3 Nanograms per milliliter | Standard Error 439.2 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Sputum Elastase Activity | Day 14, n=3,8 | 66.1 Nanograms per milliliter | Standard Error 45.64 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Sputum Elastase Activity | Day 7, n=3,6 | 238.0 Nanograms per milliliter | Standard Error 224.5 |
Secondary
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.
Time frame: Baseline (Day 1), Day 7 and Day 14
Population: Primary Completer Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Sputum NETs Quantified by Deoxyribonucleic Acid (DNA)-Elastase Complexes | Day 7, n=3,6 | 1.83 Units per milliliter | Standard Error 4.61 |
| Placebo | Change From Baseline in Sputum NETs Quantified by Deoxyribonucleic Acid (DNA)-Elastase Complexes | Day 14, n=3,8 | -4.53 Units per milliliter | Standard Error 2.696 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Sputum NETs Quantified by Deoxyribonucleic Acid (DNA)-Elastase Complexes | Day 7, n=3,6 | 0.63 Units per milliliter | Standard Error 1.859 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Sputum NETs Quantified by Deoxyribonucleic Acid (DNA)-Elastase Complexes | Day 14, n=3,8 | 2.08 Units per milliliter | Standard Error 4.072 |
Secondary
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.
Time frame: Baseline (Day 1), Day 7 and Day 14
Population: Primary Completer Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Sputum Resistin Levels | Day 7, n=3,6 | 8.93 Nanograms per milliliter | Standard Error 15.513 |
| Placebo | Change From Baseline in Sputum Resistin Levels | Day 14, n=3,8 | 15.28 Nanograms per milliliter | Standard Error 27.619 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Sputum Resistin Levels | Day 7, n=3,6 | -2.01 Nanograms per milliliter | Standard Error 4.629 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Sputum Resistin Levels | Day 14, n=3,8 | 2.61 Nanograms per milliliter | Standard Error 2.711 |
Secondary
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.
Time frame: Baseline (Day 1), Day 7 and Day 14
Population: Modified Intent-to-Treat Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP, Day 7 | -11.2 Millimeters of mercury | Standard Deviation 17.01 |
| Placebo | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP, Day 14 | -1.4 Millimeters of mercury | Standard Deviation 16.1 |
| Placebo | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | DBP, Day 14 | 2.6 Millimeters of mercury | Standard Deviation 11.01 |
| Placebo | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | DBP, Day 7 | -2.2 Millimeters of mercury | Standard Deviation 9.91 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | DBP, Day 14 | -5.3 Millimeters of mercury | Standard Deviation 7.98 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP, Day 7 | -4.1 Millimeters of mercury | Standard Deviation 17.7 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | SBP, Day 14 | -5.3 Millimeters of mercury | Standard Deviation 15.77 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) | DBP, Day 7 | -2.1 Millimeters of mercury | Standard Deviation 10.34 |
Secondary
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.
Time frame: Baseline (Day 1) and Day 14
Population: Primary Completer Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in the Ratio of Sputum NETs to Sputum Neutrophils | 0.5200 Ratio | Standard Error 0.41 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in the Ratio of Sputum NETs to Sputum Neutrophils | 0.4557 Ratio | Standard Error 0.53149 |
Secondary
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.
Time frame: Baseline (Day 1) and Day 14
Population: Modified Intent-to-Treat Population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Urinalysis Parameter: Potential of Hydrogen (pH) | 1.00 pH | Standard Deviation 1.225 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Urinalysis Parameter: Potential of Hydrogen (pH) | -0.25 pH | Standard Deviation 0.672 |
Secondary
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.
Time frame: Baseline (Day 1) and Day 14
Population: Modified Intent-to-Treat Population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Urinalysis Parameter: Specific Gravity | 0.0030 Unitless | Standard Deviation 0.00908 |
| Danirixin Hydrobromide 35 mg | Change From Baseline in Urinalysis Parameter: Specific Gravity | 0.0046 Unitless | Standard Deviation 0.00887 |
Secondary
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).
Time frame: Days 1 and 14: Pre-dose and 0.5, 1, 2 and 4 hours post-dose
Population: PK Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Maximum Observed Concentration (Cmax) of Danirixin | Day 1, n=14 | 855.2 Nanograms per milliliter | Geometric Coefficient of Variation 52.29 |
| Placebo | Maximum Observed Concentration (Cmax) of Danirixin | Day 14, n=13 | 1135.2 Nanograms per milliliter | Geometric Coefficient of Variation 65.73 |
Secondary
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.
Time frame: Up to Day 21
Population: Modified Intent-to-Treat Population.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 3 Participants |
| Placebo | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
| Danirixin Hydrobromide 35 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 6 Participants |
| Danirixin Hydrobromide 35 mg | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 Participants |
Secondary
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.
Time frame: Baseline (Day 1) and Day 14
Population: Modified Intent-to-Treat Population. Only those participants with data available at the specified data points were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Percentage Change From Baseline in Peripheral Blood Neutrophil NETs Formation Quantified by Microscopy | Not PMA stimulated | 927.5 Percent change | Standard Error 585.03 |
| Placebo | Percentage Change From Baseline in Peripheral Blood Neutrophil NETs Formation Quantified by Microscopy | PMA stimulated | 44.7 Percent change | Standard Error 41.79 |
| Danirixin Hydrobromide 35 mg | Percentage Change From Baseline in Peripheral Blood Neutrophil NETs Formation Quantified by Microscopy | PMA stimulated | 90.6 Percent change | Standard Error 60.33 |
| Danirixin Hydrobromide 35 mg | Percentage Change From Baseline in Peripheral Blood Neutrophil NETs Formation Quantified by Microscopy | Not PMA stimulated | 560.5 Percent change | Standard Error 395.72 |
Secondary
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.
Time frame: Day 1 and Day 14
Population: Modified Intent-to-Treat Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Spirometry: Forced Expiratory Volume in One Second (FEV1) at Indicated Time Points | Day 1 | 2.458 Liter | Standard Deviation 0.6331 |
| Placebo | Spirometry: Forced Expiratory Volume in One Second (FEV1) at Indicated Time Points | Day 14 | 2.344 Liter | Standard Deviation 0.7174 |
| Danirixin Hydrobromide 35 mg | Spirometry: Forced Expiratory Volume in One Second (FEV1) at Indicated Time Points | Day 1 | 1.914 Liter | Standard Deviation 0.7267 |
| Danirixin Hydrobromide 35 mg | Spirometry: Forced Expiratory Volume in One Second (FEV1) at Indicated Time Points | Day 14 | 1.910 Liter | Standard Deviation 0.7428 |
Secondary
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.
Time frame: Day 1 and Day 14
Population: Modified Intent-to-Treat Population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Spirometry: Forced Vital Capacity (FVC) at Indicated Time Points | Day 1 | 4.026 Liter | Standard Deviation 1.2021 |
| Placebo | Spirometry: Forced Vital Capacity (FVC) at Indicated Time Points | Day 14 | 4.036 Liter | Standard Deviation 1.3992 |
| Danirixin Hydrobromide 35 mg | Spirometry: Forced Vital Capacity (FVC) at Indicated Time Points | Day 1 | 3.416 Liter | Standard Deviation 1.1304 |
| Danirixin Hydrobromide 35 mg | Spirometry: Forced Vital Capacity (FVC) at Indicated Time Points | Day 14 | 3.369 Liter | Standard Deviation 1.1456 |
Secondary
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.
Time frame: Days 1 and 14: Pre-dose and 0.5, 1, 2 and 4 hours post-dose
Population: PK Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Time of Last Observed Concentration (Tlast) of Danirixin | Day 1, n=14 | 4.000 Hours |
| Placebo | Time of Last Observed Concentration (Tlast) of Danirixin | Day 14, n=13 | 4.000 Hours |
Secondary
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.
Time frame: Days 1 and 14: Pre-dose and 0.5, 1, 2 and 4 hours post-dose
Population: PK Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Placebo | Time to Cmax (Tmax) of Danirixin | Day 1, n=14 | 1.000 Hours |
| Placebo | Time to Cmax (Tmax) of Danirixin | Day 14, n=13 | 1.000 Hours |