Danirixin Dose Ranging Study in Participants With Chronic Obstructive Pulmonary Disease (COPD)

Sponsor

GlaxoSmithKline (Industry)

Overall Status

Completed

CT.gov ID

NCT03034967

Collaborator

(none)

614

Enrollment

Locations

Arms

17.3

Actual Duration (Months)

9.6

Patients Per Site

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Danirixin (DNX) is a selective CXC chemokine receptor (CXCR2) antagonist being developed as a potential anti-inflammatory agent for the treatment of COPD. This is a Phase 2, randomized, double-blind (Sponsor Open) study. The primary objective of the study is to evaluate the clinical activity and safety of danirixin compared with placebo in participants with COPD. Following baseline assessments collected over a 7 day period participants will be randomized (1:1:1:1:1:1) to receive one of five dose strengths of danirixin (5 milligram [mg], 10 mg, 25 mg, 35 mg and 50 mg) or placebo. Study treatment will be administered orally twice daily for 24 weeks. Participants will continue with their standard of care inhaled medications (i.e. long acting bronchodilators with or without inhaled corticosteroids) while receiving study treatment. Follow up will continue up to 28 days post last dose. Approximately 700 participants will be screened with a target of 540 participants completing 24 weeks of treatment and key study assessments.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Disease, Chronic Obstructive	Drug: Danirixin Drug: Danirixin matching placebo Drug: Standard of care Drug: Rescue medication	Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

614 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

Randomised, Double-Blind (Sponsor Open), Placebo-Controlled, Multicentre, Dose Ranging Study to Evaluate the Efficacy and Safety of Danirixin Tablets Administered Twice Daily Compared With Placebo for 24 Weeks in Adult Participants With Chronic Obstructive Pulmonary Disease (COPD)

Actual Study Start Date :

Apr 25, 2017

Actual Primary Completion Date :

Oct 5, 2018

Actual Study Completion Date :

Oct 5, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Danirixin 5 mg Eligible participants will receive danirixin 5 mg tablet with food twice daily along with standard care of treatment for 24 weeks.	Drug: Danirixin Danirixin is available as 5, 10, 25, 35 and 50 mg white, film-coated, oval or round shaped tablets for oral administration. Drug: Standard of care Participants will continue with their standard of care inhaled medications (i.e. long acting bronchodilators with or without inhaled corticosteroids) during the study treatment. Drug: Rescue medication Participants will continue to use rescue medication(s). The following rescue medications may be used: short acting beta agonists, short acting muscarinic antagonists, or short acting combination bronchodilators.
Experimental: Danirixin 10 mg Eligible participants will receive danirixin 10 mg tablet with food twice daily along with standard care of treatment for 24 weeks.	Drug: Danirixin Danirixin is available as 5, 10, 25, 35 and 50 mg white, film-coated, oval or round shaped tablets for oral administration. Drug: Standard of care Participants will continue with their standard of care inhaled medications (i.e. long acting bronchodilators with or without inhaled corticosteroids) during the study treatment. Drug: Rescue medication Participants will continue to use rescue medication(s). The following rescue medications may be used: short acting beta agonists, short acting muscarinic antagonists, or short acting combination bronchodilators.
Experimental: Danirixin 25 mg Eligible participants will receive danirixin 25 mg tablet with food twice daily along with standard care of treatment for 24 weeks.	Drug: Danirixin Danirixin is available as 5, 10, 25, 35 and 50 mg white, film-coated, oval or round shaped tablets for oral administration. Drug: Standard of care Participants will continue with their standard of care inhaled medications (i.e. long acting bronchodilators with or without inhaled corticosteroids) during the study treatment. Drug: Rescue medication Participants will continue to use rescue medication(s). The following rescue medications may be used: short acting beta agonists, short acting muscarinic antagonists, or short acting combination bronchodilators.
Experimental: Danirixin 35 mg Eligible participants will receive danirixin 35 mg tablet with food twice daily along with standard care of treatment for 24 weeks.	Drug: Danirixin Danirixin is available as 5, 10, 25, 35 and 50 mg white, film-coated, oval or round shaped tablets for oral administration. Drug: Standard of care Participants will continue with their standard of care inhaled medications (i.e. long acting bronchodilators with or without inhaled corticosteroids) during the study treatment. Drug: Rescue medication Participants will continue to use rescue medication(s). The following rescue medications may be used: short acting beta agonists, short acting muscarinic antagonists, or short acting combination bronchodilators.
Experimental: Danirixin 50 mg Eligible participants will receive danirixin 50 mg tablet with food twice daily along with standard care of treatment for 24 weeks.	Drug: Danirixin Danirixin is available as 5, 10, 25, 35 and 50 mg white, film-coated, oval or round shaped tablets for oral administration. Drug: Standard of care Participants will continue with their standard of care inhaled medications (i.e. long acting bronchodilators with or without inhaled corticosteroids) during the study treatment. Drug: Rescue medication Participants will continue to use rescue medication(s). The following rescue medications may be used: short acting beta agonists, short acting muscarinic antagonists, or short acting combination bronchodilators.
Placebo Comparator: Placebo Eligible participants will receive placebo tablet with food twice daily along with standard care of treatment for 24 weeks.	Drug: Danirixin matching placebo Danirixin matching placebo will be available as white, film-coated, oval or round shaped tablets for oral administration. Drug: Standard of care Participants will continue with their standard of care inhaled medications (i.e. long acting bronchodilators with or without inhaled corticosteroids) during the study treatment. Drug: Rescue medication Participants will continue to use rescue medication(s). The following rescue medications may be used: short acting beta agonists, short acting muscarinic antagonists, or short acting combination bronchodilators.

Outcome Measures

Primary Outcome Measures

Change From Baseline in Respiratory Symptoms Measured by Evaluating Respiratory Symptoms (E-RS) in COPD. E-RS: COPD Total Score [Baseline and Month 6]
E-RS: COPD is a subset of Exacerbations of Chronic pulmonary Disease Tool (EXACT). E-RS is a tool that consists of 11 items from the 14 item EXACT instrument. The domains include: respiratory symptoms (RS)-breathlessness (RS-BRL comprised of 5 items, score range [0-17]), RS-cough and sputum (RS-CSP comprised of 3 items, score range [0-11]), and RS-chest symptoms (RS-CSY comprised of 3 items, score range [0-12]). The total score ranged between 0-40 and higher values indicates severe respiratory symptoms. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Per protocol population included all participants from the mITT population who did not have a protocol deviation considered to impact efficacy. Posterior mean change and standard deviation has been presented.
Change From Baseline in Respiratory Symptoms Measured by E-RS in COPD (E-RS: COPD Breathlessness Score) [Baseline and Month 6]
E-RS: COPD is a subset of EXACT. E-RS is a tool that consists of 11 items from the 14 item EXACT instrument. The domains include: RS-BRL comprised of 5 items, score range (0-17), RS-CSP comprised of 3 items, score range (0-11), and RS-CSY comprised of 3 items, score range (0-12). The total score ranged between 0-40 and higher values indicates severe respiratory symptoms. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Posterior mean change and standard deviation has been presented.
Change From Baseline in Respiratory Symptoms Measured by E-RS in COPD (E-RS: COPD Cough and Sputum Score) [Baseline and Month 6]
E-RS: COPD is a subset of EXACT. E-RS is a tool that consists of 11 items from the 14 item EXACT instrument. The domains include: RS-BRL comprised of 5 items, score range (0-17), RS-CSP comprised of 3 items, score range (0-11), and RS-CSY comprised of 3 items, score range (0-12). The total score ranged between 0-40 and higher values indicates severe respiratory symptoms. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Posterior mean change and standard deviation has been presented.
Change From Baseline in Respiratory Symptoms Measured by E-RS in COPD (E-RS: COPD Chest Symptoms Score) [Baseline and Month 6]
E-RS: COPD is a subset of EXACT. E-RS is a tool that consists of 11 items from the 14 item EXACT instrument. The domains include: RS-BRL comprised of 5 items, score range (0-17), RS-CSP comprised of 3 items, score range (0-11), and RS-CSY comprised of 3 items, score range (0-12). The total score ranged between 0-40 and higher values indicates severe respiratory symptoms. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Posterior mean change and standard deviation has been presented.
Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE) [Up to Day 196]
AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment is categorized as SAE.
Number of Participants With Worst Case Hematology Parameter Results by Potential Clinical Importance (PCI) [Up to Day 196]
Blood samples were collected from participants for analysis of following hematology parameters with PCI low and high values: Basophils % (High 5.00x), Eosinophils % (High 2.00x), Mean corpuscular hemoglobin concentration (MCHC) gram per deciliter (g/dL) (Low 0.85x, high 1.10x), Mean corpuscular hemoglobin (MCH) picograms (pg) (Low 0.85x, high 1.20x), Mean corpuscular volume (MCV) femtoliter (fL) (low 0.25x, high 2.00x), Erythrocytes (Ery.)(10^12cells/L) (Low 0.93x, high 1.07x), Hematocrit (Ratio of 1) (Low 0.50x, high 0.50x), Hemoglobin gram per liter (g/L) (Low 0.85x, high 1.20x), Leukocytes (x10^9/L) (Low 0.70x, high 1.60x), Lymphocytes % (Low 0.80x, high 1.20x), Monocytes % (Low 0.80x, high 1.60x), Neutrophils % (Low 0.65x, high 1.50x), Platelets (x10^9cells/L) (Low 0.90x, high 1.10x). Multipliers are identified by "x", otherwise actual comparison values are provided with units. Values above and below this range were considered of PCI.
Number of Participants With Worst Case Clinical Chemistry Parameter Results by PCI [Up to Day 196]
Blood samples were collected from participants for analysis of following chemistry parameters with PCI low and high values: Alanine aminotransferase (ALT) International units per liter (IU/L) (High => 3x ULN), Alkaline phosphatase (ALP) (IU/L) (High ≥ 2x ULN); Aspartate aminotransferase (AST) (IU/L) (High=> 3x ULN); Bilirubin micromole per liter (umol/L) (High ≥ 2x ULN); Calcium millimole per liter (mmol/L) (Low 0.85x, high 1.08x), Chloride (mmol/L) (Low 0.90x, high 1.10x), Creatinine (umol/L) (High 1.30x), Direct bilirubin (umol/L) (High ≥ 2x ULN), Glucose (mmol/L) (Low <0.6x, high >4x), Potassium (mmol/L) (Low 0.75x, high 1.30x); Protein (g/L) (High 1.25x), Sodium (mmol/L) (Low 0.80x, high 1.15x), Multipliers are identified by "x", otherwise actual comparison values are provided with units. Values above and below this range were considered of PCI.
Number of Participants With Worst Case Vital Signs Parameter Results by PCI [Up to Day 168]
Vital signs parameters includes systolic blood pressure (SBP) and diastolic blood pressure (DBP), pulse rate and respiration rate were measured in a semi-supine position after 5 minutes rest for the participants at indicated time points. PCI ranges for vital signs parameters were as follows: <90 to >160 millimeters of mercury (mmHg) for SBP and <40 to >110 mmHg for DBP, <35 or >120 beats per minute for heart rate and <8 or >30 breaths per minute for respiration rate. Values above and below this range were considered of PCI.
Number of Participants With Worst Case Post-Baseline Abnormal 12-lead Electrocardiogram (ECG) Findings [Baseline and Day 168]
Triplicate 12-lead ECG obtained to measure PR, QRS, QT, and Corrected QT intervals. Only those participants with worst case post-Baseline data have been represented for abnormal - not clinical significant and abnormal - clinical significant. Day 1 was considered as Baseline.

Secondary Outcome Measures

Number of Moderate or Severe Healthcare Resource Utilization (HCRU) Exacerbations Per Participant [Up to Day 196]
Participants with moderate or severe COPD exacerbations, i.e. breathlessness, cough, sputum production, chest congestion and chest tightness analyzed. Mild exacerbations are defined as exacerbations that did not require treatment with oral/systemic corticosteroids and/or antibiotics (not involving hospitalization, Emergency Room [ER] visit or resulting in death). Moderate exacerbations are defined as exacerbations that required treatment with oral/systemic corticosteroids and/or antibiotics (not involving hospitalization, ER visit or resulting in death). Severe exacerbations are defined as exacerbations that required hospitalization, ER visit or resulted in death. Number of moderate or severe HCRU exacerbations per participant has been presented, where 0= participants in each treatment group who did not experience an event; 1= participants in each treatment group who experienced 1 event and >=2= participants in each treatment group who experienced 2 or more events.
Number of Responders E-RS in COPD (E-RS): COPD Total Score [Month 6]
E-RS: COPD is a subset of EXACT. E-RS is a tool that consists of 11 items from the 14 item EXACT instrument. E-RS is intended to capture information related to the respiratory symptoms of COPD, i.e. breathlessness, cough, sputum production, chest congestion and chest tightness. The E-RS has a scoring range of 0-40; higher scores indicate more severe symptoms. Response is defined as an E-RS: COPD total score of 2 units below baseline or lower. Non-response is defined as an E-RS: COPD total score higher than 2 units below Baseline.
Number of EXACT Events Per Participant [Up to Day 196]
EXACT is a 14 item patient reported outcome (PRO) instrument designed to capture information on the occurrence, frequency, severity, and duration of exacerbations of disease in participants with COPD. The total score for EXACT-PRO ranges from 0-100, higher scores indicate more severe symptoms. Events were categorized as recovered, censored, or persistent worsening. Number of EXACT events per participant has been presented, where 0= participants in each treatment group who did not experience an event; 1= participants in each treatment group who experienced 1 event and >=2= participants in each treatment group who experienced 2 or more events.
Time to First EXACT Event [Up to Day 168]
The time to first on-treatment EXACT event was calculated as the onset date of the first on-treatment EXACT event minus date of start of treatment plus 1.
Severity of EXACT Event [Up to Day 168]
EXACT is a 14 item PRO instrument designed to capture information on the occurrence, frequency, severity, and duration of exacerbations of disease in participants with COPD. The total score for EXACT-PRO ranges from 0-100, higher scores indicate more severe symptoms. Severity is the highest EXACT total score during the period from onset to recovery.
EXACT Event Duration for All Events [Up to Day 168]
EXACT is a 14 item PRO instrument designed to capture information on the occurrence, frequency, severity, and duration of exacerbations of disease in participants with COPD. The total score for EXACT-PRO ranges from 0-100, higher scores indicate more severe symptoms. Severity is the highest EXACT total score during the period from onset to recovery. Duration of EXACT events has been reported.
Time to First HCRU-defined COPD Exacerbation [Up to Day 196]
The time to first on-treatment Moderate/Severe HCRU exacerbation was calculated as exacerbation onset date of first on-treatment moderate or severe on-treatment exacerbation - date of start of treatment +1.
Time to First Severe HCRU-defined COPD Exacerbation [Up to Day 196]
A COPD exacerbation defined as a severe exacerbation if it requires hospitalization or ER visit or extended observation. The time to first on-treatment Moderate/Severe HCRU exacerbation was calculated as exacerbation onset date of first on-treatment moderate or severe on-treatment exacerbation - date of start of treatment +1.
HCRU-defined Exacerbation Duration [Up to Day 196]
The duration of HCRU exacerbation were determined. The duration of the exacerbation was calculated as (exacerbation resolution date or date of death - exacerbation onset date + 1). For exacerbations which were not resolved but where the participant later died from other causes, the duration was calculated using date of death as the end date of the event.
Change From Baseline in St. George's Respiratory Questionnaire for COPD Patients (SGRQ-C) Total Score [Baseline, Days 84 and 168]
The SGRQ-C consists of 40 items aggregated into 3 component scores: Symptoms, Activity, Impacts, and a Total score. Each response to a question is assigned a weight. Component scores are calculated by summing the weights from all positive items in that component, dividing by the sum of weights for all items in that component, and multiplying this number by 100. Component scores could range from 0-100, with a higher component score indicating greater disease burden. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Posterior mean change and standard deviation has been presented.
Number of SGRQ Responder [Day 84 and Day 168]
A participant was consider Responder according to SGRQ total score if their change from Baseline SGRQ total score of 4 units below Baseline or lower.
Change From Baseline COPD Assessment Test (CAT) Total Score [Baseline, Days 84 and 168]
The CAT is an 8 item questionnaire (cough, sputum, chest tightness, breathlessness, going up hills/stairs, activity limitation at home, confidence leaving the home, and sleep and energy) that measures health status of participants with COPD. Participants were completed each question by rating their experience on a 6 point scale ranging from 0 (maximum impairment) to 5 (no impairment) with a total scoring range of 0-40; higher scores indicate worse health status. A CAT score was calculated by summing the non-missing scores on the eight items. Individual items are scored from 0 to 5 with a total score range from 0 - 40, higher scores indicate greater disease impact. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Posterior mean change and standard deviation has been presented.
Number of CAT Responder [Day 84 and Day 168]
A participant was considered as a responder according to CAT score if their change from Baseline CAT score 2.0 units below Baseline or lower.
Change From Baseline in Post-bronchodilator FEV1 as a Lung Function Assessment [Baseline, Days 84 and 168]
Spirometric analysis was done to determine FEV1. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Least square mean change from Baseline and standard error has been presented.
Percent Predicted Normal FEV1 [At Screening]
Spirometric analysis was done to determine percent predicted FEVI at screening. FEV1 is forced expiratory volume in one second. Percent predicted FEV1 is defined as the percent FEV1 of the participant is divided by average FEV1 percent in the population of any person similar age, sex and body composition.
Change From Baseline in Post-bronchodilator Forced Vital Capacity (FVC) as a Lung Function Assessment [Baseline, Days 84 and 168]
Spirometric analysis was done to determine FVC. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Least square mean change from Baseline and standard error has been presented.
Change From Baseline in Post-bronchodilator FEV1/FVC Ratio as a Lung Function Assessment [Baseline, Days 84 and 168]
Spirometric analysis was done to determine FEV1 and FVC. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.
Change From Baseline Number of Puffs of Rescue Medication Per Day [Baseline, Months 1, 2, 3, 4, 5 and 6]
The mean number of puffs of rescue per day was calculated over the same time periods and using the same assumptions as rescue use via diary. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Least square mean change from Baseline and standard error has been presented.
Participant Experience of Physical Activity Measured Using PROactive Physical Activity in COPD (C-PPAC) Questionnaire [Days 84 and 168]
The Clinical Visit PROactive Physical Activity in COPD (C-PPAC) tool is a designed for intermittent use within a clinical study. PROactive Total Score and two domain scores (amount and difficulty) are derived using data from the C-PPAC questionnaire and a physical activity monitor worn for 7 days prior to the questionnaire.C-PPAC is a 12 item questionnaire. The PROactive tools are scored from 0 to 100 with higher scores indicating greater disease impact. It was implemented in a subset of approximately 50% of participants. The amount domain is calculated using 2 items from the C-PPAC questionnaire (amount of walking outside and chores outside) and 2 activity monitor outputs (vector magnitude units per minute (VMU/min) and steps/day). Each domain score is based on the addition of items (0-15 for amount and 0-40 for difficulty) and then scaled from 0-100. The total score is calculated as (amount+difficulty)/2.
Danirixin Whole Blood Pharmacokinetic Concentration-Time Data [Pre-dose on Days 1, 56, 84 and 168; 0.5, 1, 2, 4, 6, 8, 10, 12 hours post-dose on Days 1 and 168]
Blood samples were collected from the participants for the analysis of blood pharmacokinetic concentration-time data. All participants in the mITT population who had at least 1 non-missing Pharmacokinetic assessment obtained and analyzed whilst on treatment with danirixin were included Pharmacokinetic population.
Area Under the Plasma Concentration-time Curve From Time Zero to Last Time of Quantifiable Concentration [AUC(0-t)] of Danirixin in Whole Blood Using Dried Blood Spot [Days 1 and 168]
Blood samples were collected at indicated timepoints for the analysis of phamacokinetic parameter. All participants in the PK population who had at least 1 non-missing PK assessment obtained and analyzed whilst on treatment with danirixin from a dry blood spot sample and corresponding wet whole blood sample were included in Pharmacokinetic population.
Concentration Maximum (Cmax) of Danirixin in Whole Blood Using Dried Blood Spots [Days 1 and 168]
Blood samples were collected from the participants for the analysis of pharmacokinetic parameter.
Time to Reach Maximum Plasma Concentration (Tmax) of Danirixin in Whole Blood Using Dried Blood Spots [Days 1 and 168]
Blood samples were collected from the participants for the analysis of pharmacokinetic parameter.

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria

Participants must be aged between 40 to 80 years of age inclusive, at the time of signing the informed consent.
Participants who have COPD (post bronchodilator FEV1/FVC ratio <0.7 and FEV1% predicted >=40%) based on American Thoracic Society (ATS)/European Respiratory Society (ERS) current guidelines. Participants with a historical diagnosis of asthma may be included so long as they have a current diagnosis of COPD.
History of respiratory symptoms including chronic cough, mucus hypersecretion, and dyspnea on most days for at least the previous 3 months prior to screening.
Participants with a documented history of COPD exacerbation(s) in the 12 months prior to study participation (screening) meeting at least one of the following criteria: >=2 COPD exacerbations resulting in prescription for antibiotics and/or oral corticosteroids or hospitalization or extended observation in a hospital emergency room or outpatient center; 1 COPD exacerbation resulting in prescription for antibiotics and/or oral corticosteroids of hospitalization or extended observation in a hospital emergency room or outpatient center and a plasma fibrinogen concentration at screening >=3 grams/liter (300 milligram/deciliter)
Current 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). Current smokers are defined as those who are currently smoking cigarettes (i.e. have smoked at least one cigarette daily or most days for the month prior to Visit 1). Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1.
Participants must have the ability and willingness to use an electronic diary (log pad) on a daily basis.
Body weight >=45 kilogram (kg)
Male or female: A male participant must agree to use contraception during the treatment period and for at least 60 hours after the last dose of study treatment, corresponding to approximately 6 half-lives (which is the time needed to eliminate any teratogenic study treatment) and to refrain from donating sperm during this period; A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: 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.

Exclusion Criteria

Diagnosis of other clinically relevant lung diseases (other than COPD), e.g. sarcoidosis, tuberculosis, pulmonary fibrosis, severe bronchiectasis or lung cancer.
Alpha-1-antitrypsin deficiency as the underlying cause of COPD
Pulse oximetry <88% at rest at screening. Participants should be tested while breathing room air. However, participants living at high altitudes (above 5000 feet or 1500 meters above sea level) who are receiving supplemental oxygen can be included provided they are receiving the equivalent of <4 liter per minute (L/min) and screening pulse oximetry is measured while on their usual oxygen settings.
Less than 14 days have elapsed from the completion of a course of antibiotics or oral corticosteroids for a recent COPD exacerbation.
A peripheral blood neutrophil count <1.5 x 10^9/L.
Diagnosis of pneumonia (chest X-ray or CT confirmed) within the 3 months prior to screening.
Chest x-ray (posterior-anterior with lateral) or CT scan reveals evidence of a clinically significant abnormality not believed to be due to the presence of COPD (historic results up to 1 year prior to screening may be used). For sites in Germany: If a chest x-ray (or CT scan) within 1 year prior to screening is not available, approval to conduct a diagnostic chest x-ray will need to be obtained from the Federal Office of Radiation Protection (BfS).
History or current evidence of other clinically significant medical condition that is uncontrolled on permitted therapies. Significant is defined as any disease that, in the opinion of the Investigator, would put the safety of the participant at risk through study participation, or that would affect the safety analysis or other analysis if the disease/condition worsened during the study.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
Abnormal and clinically significant 12-lead ECG finding. The investigator will determine the clinical significance of each abnormal ECG finding in relation to the participant's medical history and exclude participants who would be at undue risk by participating in the study. An abnormal and clinically significant finding that would preclude a participant from entering the study is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the following: atrial fibrillation with rapid ventricular rate >120 beats per minute (bpm); sustained or non-sustained ventricular tachycardia; second degree heart block Mobitz type II and third degree heart block (unless pacemaker or defibrillator has been implanted); Corrected QT Interval using Fridericia formula (QTcF) >=500 millisecond (msec) in participants with QRS <120 msec and QTcF >=530 msec in participants with QRS >=120 msec.
Previous lung surgery (e.g. lobectomy, pneumonectomy) or lung volume reduction procedure.
Current or expected chronic use of macrolide antibiotics during the study period for the prevention of COPD exacerbations. Examples of chronic use include, but are not limited to, daily or two to three times per week use for at least 3 months.
Oral or injectable CYP3A4 or breast cancer resistance protein (BRCP) substrates with a narrow therapeutic index (CYP3A4 substrates include, but are not limited to, alfenatil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, and theophylline; BRCP substrates include, but are not limited to, topotecan.) The Investigator should consult with the Medical Monitor if necessary.
Current or expected use of phosphodiesterase-4 inhibitors (e.g. roflumilast). Participants currently receiving roflumilast may be included if they are able to discontinue use from 30 days prior to screening through the completion of the follow up visit.
Participation in a previous clinical trial and has received an investigational product within any of the following time periods 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).
Participation in a previous clinical trial with danirixin within 1 year prior to the first dosing day in the current study
Exposure to more than four investigational products within 1 year prior to the first dosing day in the current study.
Alanine transferase (ALT) >2x upper limit of normal (ULN); bilirubin > 1.5xULN (isolated bilirubin > 1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
A positive test for human immunodeficiency virus (HIV) antibody
A positive pre-study hepatitis B surface antigen or positive hepatitis C antibody result within 3 months prior to screening.
Pulmonary rehabilitation: Participants who have taken part in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to screening or participants who plan to enter the acute phase of a pulmonary rehabilitation program during the study. Participants who are in the maintenance phase of a pulmonary rehabilitation program are not excluded.
A history of allergy or hypersensitivity to any of the ingredients in the study treatment.
A known or suspected history of alcohol or drug abuse within the 2 years prior to screening.
Inability to read: in the opinion of the Investigator, any participant who is unable to read and/or would not be able to complete study related materials.
Affiliation with the study site: study investigators, sub-investigators, study coordinators, employees of a study investigator, sub-investigator or study site, or immediate family member of any of the above that are involved with the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Birmingham	Alabama	United States	35243
2	GSK Investigational Site	Birmingham	Alabama	United States	35294
3	GSK Investigational Site	Topeka	Kansas	United States	66606
4	GSK Investigational Site	Saint Louis	Missouri	United States	63141
5	GSK Investigational Site	Greensboro	North Carolina	United States	27403
6	GSK Investigational Site	Medford	Oregon	United States	97504
7	GSK Investigational Site	Orangeburg	South Carolina	United States	29118
8	GSK Investigational Site	Spartanburg	South Carolina	United States	29303
9	GSK Investigational Site	Morgantown	West Virginia	United States	26505
10	GSK Investigational Site	Randwick	New South Wales	Australia	2031
11	GSK Investigational Site	Westmead	New South Wales	Australia	2145
12	GSK Investigational Site	Clayton	Victoria	Australia	3168
13	GSK Investigational Site	Footscray	Victoria	Australia	3011
14	GSK Investigational Site	Murdoch	Western Australia	Australia	6150
15	GSK Investigational Site	Winnipeg	Manitoba	Canada	R2K 3S8
16	GSK Investigational Site	Truro	Nova Scotia	Canada	B2N 1L2
17	GSK Investigational Site	Toronto	Ontario	Canada	M5T 3A9
18	GSK Investigational Site	Gatineau	Quebec	Canada	J8Y 6S8
19	GSK Investigational Site	St. Charles-Borromee	Quebec	Canada	J6E 2B4
20	GSK Investigational Site	Quebec		Canada	G1V 4G5
21	GSK Investigational Site	Darmstadt	Hessen	Germany	64283
22	GSK Investigational Site	Frankfurt	Hessen	Germany	60389
23	GSK Investigational Site	Frankfurt	Hessen	Germany	60596
24	GSK Investigational Site	Hannover	Niedersachsen	Germany	30173
25	GSK Investigational Site	Koblenz	Rheinland-Pfalz	Germany	56068
26	GSK Investigational Site	Leipzg	Sachsen	Germany	04109
27	GSK Investigational Site	Grosshansdorf	Schleswig-Holstein	Germany	22927
28	GSK Investigational Site	Berlin		Germany	10367
29	GSK Investigational Site	Berlin		Germany	10717
30	GSK Investigational Site	Berlin		Germany	10787
31	GSK Investigational Site	Bucheon-Si, Gyeonggi-Do		Korea, Republic of	420-021
32	GSK Investigational Site	Incheon		Korea, Republic of	403-720
33	GSK Investigational Site	Seoul		Korea, Republic of	130-709
34	GSK Investigational Site	Seoul		Korea, Republic of	130-872
35	GSK Investigational Site	Seoul		Korea, Republic of	138-736
36	GSK Investigational Site	Seoul		Korea, Republic of	156-707
37	GSK Investigational Site	Seoul		Korea, Republic of	156-755
38	GSK Investigational Site	Wonju-si, Gangwon-do		Korea, Republic of	220-701
39	GSK Investigational Site	Alkmaar		Netherlands	1815 JD
40	GSK Investigational Site	Breda		Netherlands	4818 CK
41	GSK Investigational Site	Eindhoven		Netherlands	5623 EJ
42	GSK Investigational Site	Hengelo		Netherlands	7555 DL
43	GSK Investigational Site	Hoorn		Netherlands	1624 NP
44	GSK Investigational Site	Ksawerow		Poland	95-054
45	GSK Investigational Site	Lubin		Poland	59-300
46	GSK Investigational Site	Ostrowiec Swietokrzyski		Poland	27-400
47	GSK Investigational Site	Szczecin		Poland	71-124
48	GSK Investigational Site	Wroclaw		Poland	54-239
49	GSK Investigational Site	Bacau		Romania	600252
50	GSK Investigational Site	Bucharest		Romania	050159
51	GSK Investigational Site	Cluj Napoca		Romania	400275
52	GSK Investigational Site	Cluj Napoca		Romania	400371
53	GSK Investigational Site	Constanta		Romania	900002
54	GSK Investigational Site	Focsani		Romania	620043
55	GSK Investigational Site	Iasi		Romania	700115
56	GSK Investigational Site	Ramnicu Valcea		Romania	240564
57	GSK Investigational Site	Slobozia		Romania	920013
58	GSK Investigational Site	Suceava		Romania	720237
59	GSK Investigational Site	Barcelona		Spain	08003
60	GSK Investigational Site	Madrid		Spain	28040
61	GSK Investigational Site	Pozuelo De Alarcón/Madrid		Spain	28223
62	GSK Investigational Site	Salamanca		Spain	37007
63	GSK Investigational Site	Santander		Spain	39008
64	GSK Investigational Site	Zaragoza		Spain	50009

Sponsors and Collaborators

GlaxoSmithKline

Investigators

Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

More Information

Publications

Lazaar AL, Miller BE, Donald AC, Keeley T, Ambery C, Russell J, Watz H, Tal-Singer R; for 205724 Investigators. CXCR2 antagonist for patients with chronic obstructive pulmonary disease with chronic mucus hypersecretion: a phase 2b trial. Respir Res. 2020 Jun 12;21(1):149. doi: 10.1186/s12931-020-01401-4.

Responsible Party:

GlaxoSmithKline

ClinicalTrials.gov Identifier:

NCT03034967

Other Study ID Numbers:

205724
2016-003675-21

First Posted:

Jan 27, 2017

Last Update Posted:

Oct 28, 2020

Last Verified:

Oct 1, 2020

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Keywords provided by GlaxoSmithKline

Additional relevant MeSH terms:

Lung Diseases

Lung Diseases, Obstructive

Pulmonary Disease, Chronic Obstructive

Study Results

Participant Flow

Recruitment Details	This study investigated the dose response and safety of danirixin compared with placebo in Chronic Obstructive Pulmonary Disease (COPD) participants with respiratory symptoms including cough, increased sputum production and dyspnoea.
Pre-assignment Detail	A total of 614 participants were randomized in this study across 9 countries.

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Period Title: Overall Study
STARTED	102	102	103	103	102	102
COMPLETED	88	97	90	92	88	87
NOT COMPLETED	14	5	13	11	14	15

Baseline Characteristics

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg	Total
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Total of all reporting groups
Overall Participants	102	102	103	103	102	102	614
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	66.2 (7.31)	66.3 (6.79)	65.7 (7.48)	66.3 (7.28)	65.1 (7.58)	65.7 (6.98)	65.9 (7.23)
Sex: Female, Male (Count of Participants)
Female	29 28.4%	36 35.3%	32 31.1%	38 36.9%	35 34.3%	32 31.4%	202 32.9%
Male	73 71.6%	66 64.7%	71 68.9%	65 63.1%	67 65.7%	70 68.6%	412 67.1%
Race/Ethnicity, Customized (Count of Participants)
Asian - East Asian Heritage	10 9.8%	6 5.9%	18 17.5%	17 16.5%	10 9.8%	17 16.7%	78 12.7%
Asian - South East Asian Heritage	1 1%	0 0%	0 0%	0 0%	0 0%	0 0%	1 0.2%
Black or African American	2 2%	2 2%	1 1%	0 0%	0 0%	1 1%	6 1%
Native Hawaiian or other Pacific Islander	1 1%	0 0%	0 0%	0 0%	0 0%	0 0%	1 0.2%
White - Arabic/North African Heritage	1 1%	1 1%	0 0%	0 0%	0 0%	0 0%	2 0.3%
White - White/Caucasian/European Heritage	87 85.3%	93 91.2%	84 81.6%	86 83.5%	92 90.2%	84 82.4%	526 85.7%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Respiratory Symptoms Measured by Evaluating Respiratory Symptoms (E-RS) in COPD. E-RS: COPD Total Score
Description	E-RS: COPD is a subset of Exacerbations of Chronic pulmonary Disease Tool (EXACT). E-RS is a tool that consists of 11 items from the 14 item EXACT instrument. The domains include: respiratory symptoms (RS)-breathlessness (RS-BRL comprised of 5 items, score range [0-17]), RS-cough and sputum (RS-CSP comprised of 3 items, score range [0-11]), and RS-chest symptoms (RS-CSY comprised of 3 items, score range [0-12]). The total score ranged between 0-40 and higher values indicates severe respiratory symptoms. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Per protocol population included all participants from the mITT population who did not have a protocol deviation considered to impact efficacy. Posterior mean change and standard deviation has been presented.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description
Per Protocol Population. Only those participants with data available at the specified data points was analyzed.

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	86	95	87	91	85	86
Mean (Standard Deviation) [Scores on a scale]	-2.11 (0.345)	-1.93 (0.289)	-1.47 (0.349)	-0.87 (0.286)	-0.76 (0.259)	-0.71 (0.281)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 5 mg
	Comments	4-parameter Emax model selected.
	Type of Statistical Test	Other
	Comments	Emax

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Median Posterior Difference
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 90% 0.00 to 0.66
	Parameter Dispersion	Type: Value:
	Estimation Comments	Median posterior difference, 90 percent (%) credible interval for Placebo and Danirixin 5 mg has been presented.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 10 mg
	Comments	4-parameter Emax model
	Type of Statistical Test	Other
	Comments	Emax

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Median Posterior Difference
	Estimated Value	0.61
	Confidence Interval	(2-Sided) 90% 0.00 to 1.52
	Parameter Dispersion	Type: Value:
	Estimation Comments	Median posterior difference, 90% credible interval for Placebo and Danirixin 10 mg has been presented.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 25 mg
	Comments	4-parameter Emax model selected.
	Type of Statistical Test	Other
	Comments	Emax

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Median Posterior Difference
	Estimated Value	1.25
	Confidence Interval	(2-Sided) 90% 0.43 to 1.97
	Parameter Dispersion	Type: Value:
	Estimation Comments	Median posterior difference, 90% credible interval for Placebo and Danirixin 25 mg has been presented.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 35 mg
	Comments	4-parameter Emax model selected.
	Type of Statistical Test	Other
	Comments	Emax

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Median Posterior Difference
	Estimated Value	1.34
	Confidence Interval	(2-Sided) 90% 0.72 to 2.03
	Parameter Dispersion	Type: Value:
	Estimation Comments	Median posterior difference, 90% credible interval for Placebo and Danirixin 35 mg has been presented.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 50 mg
	Comments	4-parameter Emax model selected.
	Type of Statistical Test	Other
	Comments	Emax

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Median Posterior Difference
	Estimated Value	1.38
	Confidence Interval	(2-Sided) 90% 0.79 to 2.07
	Parameter Dispersion	Type: Value:
	Estimation Comments	Median posterior difference, 90% credible interval for Placebo and Danirixin 50 mg has been presented.

2. Primary Outcome

Title	Change From Baseline in Respiratory Symptoms Measured by E-RS in COPD (E-RS: COPD Breathlessness Score)
Description	E-RS: COPD is a subset of EXACT. E-RS is a tool that consists of 11 items from the 14 item EXACT instrument. The domains include: RS-BRL comprised of 5 items, score range (0-17), RS-CSP comprised of 3 items, score range (0-11), and RS-CSY comprised of 3 items, score range (0-12). The total score ranged between 0-40 and higher values indicates severe respiratory symptoms. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Posterior mean change and standard deviation has been presented.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description
Per Protocol Population. Only those participants with available data at the specified time points were analyzed.

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	86	95	87	91	85	86
Mean (Standard Deviation) [Scores on a scale]	-0.82 (0.202)	-0.69 (0.162)	-0.41 (0.183)	-0.15 (0.148)	-0.10 (0.141)	-0.09 (0.158)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 5 mg
	Comments	4-parameter Emax model selected.
	Type of Statistical Test	Other
	Comments	Emax

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Median Posterior Difference
	Estimated Value	0.09
	Confidence Interval	(2-Sided) 90% 0.00 to 0.42
	Parameter Dispersion	Type: Value:
	Estimation Comments	Median posterior difference, 90% credible interval for Placebo and Danirixin 5 mg has been presented.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 10 mg
	Comments	4-parameter Emax model
	Type of Statistical Test	Other
	Comments	Emax

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Median Posterior Difference
	Estimated Value	0.43
	Confidence Interval	(2-Sided) 90% 0.00 to 0.87
	Parameter Dispersion	Type: Value:
	Estimation Comments	Median posterior difference, 90% credible interval for Placebo and Danirixin 10 mg has been presented.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 25 mg
	Comments	4-parameter Emax model selected.
	Type of Statistical Test	Other
	Comments	Emax

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Median Posterior Difference
	Estimated Value	0.68
	Confidence Interval	(2-Sided) 90% 0.23 to 1.08
	Parameter Dispersion	Type: Value:
	Estimation Comments	Median posterior difference, 90% credible interval for Placebo and Danirixin 25 mg has been presented.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 35 mg
	Comments	4-parameter Emax model selected.
	Type of Statistical Test	Other
	Comments	Emax

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Median Posterior Difference
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 90% 0.37 to 1.10
	Parameter Dispersion	Type: Value:
	Estimation Comments	Median posterior difference, 90% credible interval for Placebo and Danirixin 35 mg has been presented.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 50 mg
	Comments	4-parameter Emax model selected.
	Type of Statistical Test	Other
	Comments	Emax

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Median Posterior Difference
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 90% 0.40 to 1.12
	Parameter Dispersion	Type: Value:
	Estimation Comments	Median posterior difference, 90% credible interval for Placebo and Danirixin 50 mg has been presented.

3. Primary Outcome

Title	Change From Baseline in Respiratory Symptoms Measured by E-RS in COPD (E-RS: COPD Cough and Sputum Score)
Description	E-RS: COPD is a subset of EXACT. E-RS is a tool that consists of 11 items from the 14 item EXACT instrument. The domains include: RS-BRL comprised of 5 items, score range (0-17), RS-CSP comprised of 3 items, score range (0-11), and RS-CSY comprised of 3 items, score range (0-12). The total score ranged between 0-40 and higher values indicates severe respiratory symptoms. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Posterior mean change and standard deviation has been presented.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description
Per Protocol Population. Only those participants with available data at the specified time points were analyzed.

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	86	95	87	91	85	86
Mean (Standard Deviation) [Scores on a scale]	-0.83 (0.107)	-0.79 (0.090)	-0.67 (0.109)	-0.46 (0.104)	-0.40 (0.088)	-0.37 (0.098)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 5 mg
	Comments	4-parameter Emax model selected.
	Type of Statistical Test	Other
	Comments	Emax

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Median Posterior Difference
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 90% 0.00 to 0.16
	Parameter Dispersion	Type: Value:
	Estimation Comments	Median posterior difference, 90% credible interval for Placebo and Danirixin 5 mg has been presented.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 10 mg
	Comments	4-parameter Emax model
	Type of Statistical Test	Other
	Comments	Emax

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Median Posterior Difference
	Estimated Value	0.12
	Confidence Interval	(2-Sided) 90% 0.00 to 0.43
	Parameter Dispersion	Type: Value:
	Estimation Comments	Median posterior difference, 90% credible interval for Placebo and Danirixin 10 mg has been presented.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 25 mg
	Comments	4-parameter Emax model selected.
	Type of Statistical Test	Other
	Comments	Emax

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Median Posterior Difference
	Estimated Value	0.38
	Confidence Interval	(2-Sided) 90% 0.04 to 0.61
	Parameter Dispersion	Type: Value:
	Estimation Comments	Median posterior difference, 90% credible interval for Placebo and Danirixin 25 mg has been presented.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 35 mg
	Comments	4-parameter Emax model selected.
	Type of Statistical Test	Other
	Comments	Emax

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Median Posterior Difference
	Estimated Value	0.42
	Confidence Interval	(2-Sided) 90% 0.21 to 0.64
	Parameter Dispersion	Type: Value:
	Estimation Comments	Median posterior difference, 90% credible interval for Placebo and Danirixin 35 mg has been presented.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 50 mg
	Comments	4-parameter Emax model selected.
	Type of Statistical Test	Other
	Comments	Emax

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Median Posterior Difference
	Estimated Value	0.45
	Confidence Interval	(2-Sided) 90% 0.26 to 0.66
	Parameter Dispersion	Type: Value:
	Estimation Comments	Median posterior difference, 90% credible interval for Placebo and Danirixin 50 mg has been presented.

4. Primary Outcome

Title	Change From Baseline in Respiratory Symptoms Measured by E-RS in COPD (E-RS: COPD Chest Symptoms Score)
Description	E-RS: COPD is a subset of EXACT. E-RS is a tool that consists of 11 items from the 14 item EXACT instrument. The domains include: RS-BRL comprised of 5 items, score range (0-17), RS-CSP comprised of 3 items, score range (0-11), and RS-CSY comprised of 3 items, score range (0-12). The total score ranged between 0-40 and higher values indicates severe respiratory symptoms. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Posterior mean change and standard deviation has been presented.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description
Per Protocol Population. Only those participants with data available at the specified data points were analyzed.

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	86	95	87	91	85	86
Mean (Standard Deviation) [Scores on a scale]	-0.36 (0.148)	-0.35 (0.061)	-0.34 (0.062)	-0.34 (0.069)	-0.34 (0.073)	-0.34 (0.078)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 5 mg
	Comments	Log-linear model.
	Type of Statistical Test	Other
	Comments	Log-linear

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Median Posterior Difference
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 90% -0.21 to 0.23
	Parameter Dispersion	Type: Value:
	Estimation Comments	Median posterior difference, 90% credible interval for Placebo and Danirixin 5 mg has been presented.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 10 mg
	Comments	Log-linear model
	Type of Statistical Test	Other
	Comments	Log-linear

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Median Posterior Difference
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 90% -0.23 to 0.25
	Parameter Dispersion	Type: Value:
	Estimation Comments	Median posterior difference, 90% credible interval for Placebo and Danirixin 10 mg has been presented.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 25 mg
	Comments	Log-linear model
	Type of Statistical Test	Other
	Comments	Log-linear

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Median Posterior Difference
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 90% -0.27 to 0.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	Median posterior difference, 90% credible interval for Placebo and Danirixin 25 mg has been presented.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 35 mg
	Comments	Log-linear model
	Type of Statistical Test	Other
	Comments	Log-linear

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Median Posterior Difference
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 90% -0.28 to 0.30
	Parameter Dispersion	Type: Value:
	Estimation Comments	Median posterior difference, 90% credible interval for Placebo and Danirixin 35 mg has been presented.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 50 mg
	Comments	Log-linear model
	Type of Statistical Test	Other
	Comments	Log-linear

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Median Posterior Difference
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 90% -0.29 to 0.31
	Parameter Dispersion	Type: Value:
	Estimation Comments	Median posterior difference, 90% credible interval for Placebo and Danirixin 50 mg has been presented.

5. Primary Outcome

Title	Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
Description	AE is any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. SAE is any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect or any other situation according to medical or scientific judgment is categorized as SAE.
Time Frame	Up to Day 196

Outcome Measure Data

Analysis Population Description
Modified Intent-to-Treat (mITT) population. mIIT population comprised of all randomized participants who were randomized apart from those randomized in error, received a treatment randomization number, modified and data for this population were based on actual treatment received.

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	102	102	103	103	102	102
Any AE	63 61.8%	63 61.8%	69 67%	68 66%	63 61.8%	71 69.6%
Any SAE	8 7.8%	7 6.9%	13 12.6%	10 9.7%	7 6.9%	11 10.8%

6. Primary Outcome

Title	Number of Participants With Worst Case Hematology Parameter Results by Potential Clinical Importance (PCI)
Description	Blood samples were collected from participants for analysis of following hematology parameters with PCI low and high values: Basophils % (High 5.00x), Eosinophils % (High 2.00x), Mean corpuscular hemoglobin concentration (MCHC) gram per deciliter (g/dL) (Low 0.85x, high 1.10x), Mean corpuscular hemoglobin (MCH) picograms (pg) (Low 0.85x, high 1.20x), Mean corpuscular volume (MCV) femtoliter (fL) (low 0.25x, high 2.00x), Erythrocytes (Ery.)(10^12cells/L) (Low 0.93x, high 1.07x), Hematocrit (Ratio of 1) (Low 0.50x, high 0.50x), Hemoglobin gram per liter (g/L) (Low 0.85x, high 1.20x), Leukocytes (x10^9/L) (Low 0.70x, high 1.60x), Lymphocytes % (Low 0.80x, high 1.20x), Monocytes % (Low 0.80x, high 1.60x), Neutrophils % (Low 0.65x, high 1.50x), Platelets (x10^9cells/L) (Low 0.90x, high 1.10x). Multipliers are identified by "x", otherwise actual comparison values are provided with units. Values above and below this range were considered of PCI.
Time Frame	Up to Day 196

Outcome Measure Data

Analysis Population Description
mITT population. Only those participants with available data at the specified time points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	102	102	103	103	102	102
Basophils, No change, n=97, 102, 101, 101, 101, 99	97 95.1%	102 100%	101 98.1%	101 98.1%	101 99%	99 97.1%
Basophils, High, n=97, 102, 101, 101, 101, 99	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Eosinophils,No change,n=97,102,101,101,101,99	97 95.1%	101 99%	101 98.1%	98 95.1%	100 98%	98 96.1%
Eosinophils, High, n=97, 102, 101, 101, 101, 99	0 0%	1 1%	0 0%	3 2.9%	1 1%	1 1%
Ery. MCHC, Low, n=97, 102, 101, 101, 102, 99	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Ery. MCHC,No change,n=97,102,101,101,102,99	97 95.1%	102 100%	101 98.1%	101 98.1%	102 100%	99 97.1%
Ery. MCHC, High, n=97, 102, 101, 101, 102, 99	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Ery. MCH, Low, n=97, 102, 101, 101, 102, 99	0 0%	0 0%	0 0%	0 0%	0 0%	1 1%
Ery. MCH, No Change, n=97, 102, 101, 101, 102, 99	97 95.1%	102 100%	101 98.1%	101 98.1%	102 100%	98 96.1%
Ery. MCH, High, n=97, 102, 101, 101, 102, 99	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Ery. MCV, Low, n=97, 102, 101, 101, 102, 99	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Ery. MCV, No Change, n=97, 102, 101, 101, 102, 99	97 95.1%	102 100%	101 98.1%	101 98.1%	102 100%	99 97.1%
Ery. MCV, High, n=97, 102, 101, 101, 102, 99	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Erythrocytes, Low, n=97, 102, 101, 101, 102, 99	2 2%	1 1%	3 2.9%	3 2.9%	2 2%	2 2%
Erythrocytes, No change,n=97,102,101,101,102,99	93 91.2%	99 97.1%	97 94.2%	97 94.2%	99 97.1%	97 95.1%
Erythrocytes. High, n=97, 102, 101, 101, 102, 99	2 2%	2 2%	1 1%	1 1%	1 1%	0 0%
Hematocrit, Low, n=97, 102, 101, 101, 102, 99	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Hematocrit, No Change, n=97,102,101,101,102,99	97 95.1%	102 100%	101 98.1%	101 98.1%	102 100%	99 97.1%
Hematocrit, High, n=97, 102, 101, 101, 102, 99	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Hemoglobin, Low, n=97, 102, 101, 101, 102, 99	1 1%	1 1%	2 1.9%	0 0%	2 2%	0 0%
Hemoglobin, No change, n=97,102,101,101,102,99	96 94.1%	101 99%	99 96.1%	101 98.1%	100 98%	99 97.1%
Hemoglobin, High, n=97, 102, 101, 101, 102, 99	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Leukocytes, Low, n=97, 102, 101, 101, 102, 99	0 0%	0 0%	0 0%	0 0%	0 0%	1 1%
Leukocytes, No change, n=97,102,101,101,102,99	97 95.1%	102 100%	101 98.1%	101 98.1%	102 100%	98 96.1%
Leukocytes, High, n=97, 102, 101, 101, 102, 99	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Lymphocytes, Low, n=97, 102, 101, 101, 101, 99	3 2.9%	7 6.9%	5 4.9%	8 7.8%	7 6.9%	4 3.9%
Lymphocytes, No change, n=97,102,101,101,101,99	94 92.2%	95 93.1%	96 93.2%	92 89.3%	93 91.2%	94 92.2%
Lymphocytes, High, n=97, 102, 101, 101, 101, 99	0 0%	0 0%	0 0%	1 1%	1 1%	1 1%
Monocytes, No change, n=97, 102, 101, 101, 101, 99	97 95.1%	101 99%	99 96.1%	101 98.1%	100 98%	98 96.1%
Monocytes, High, n=97, 102, 101, 101, 101, 99	0 0%	1 1%	2 1.9%	0 0%	1 1%	1 1%
Neutrophils, Low, n=97, 102, 101, 101, 101, 99	0 0%	0 0%	0 0%	1 1%	3 2.9%	1 1%
Neutrophils, No change, n=97,102,101,101,101,99	97 95.1%	102 100%	101 98.1%	100 97.1%	98 96.1%	98 96.1%
Neutrophils, High, n=97, 102, 101, 101, 101, 99	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Platelets, Low, n=97, 102, 101, 101, 101, 99	0 0%	1 1%	0 0%	0 0%	0 0%	0 0%
Platelets, No change, n=97, 102, 101, 101, 101, 99	97 95.1%	99 97.1%	100 97.1%	101 98.1%	99 97.1%	99 97.1%
Platelets, High, n=97, 102, 101, 101, 101, 99	0 0%	2 2%	1 1%	0 0%	2 2%	0 0%

7. Primary Outcome

Title	Number of Participants With Worst Case Clinical Chemistry Parameter Results by PCI
Description	Blood samples were collected from participants for analysis of following chemistry parameters with PCI low and high values: Alanine aminotransferase (ALT) International units per liter (IU/L) (High => 3x ULN), Alkaline phosphatase (ALP) (IU/L) (High ≥ 2x ULN); Aspartate aminotransferase (AST) (IU/L) (High=> 3x ULN); Bilirubin micromole per liter (umol/L) (High ≥ 2x ULN); Calcium millimole per liter (mmol/L) (Low 0.85x, high 1.08x), Chloride (mmol/L) (Low 0.90x, high 1.10x), Creatinine (umol/L) (High 1.30x), Direct bilirubin (umol/L) (High ≥ 2x ULN), Glucose (mmol/L) (Low <0.6x, high >4x), Potassium (mmol/L) (Low 0.75x, high 1.30x); Protein (g/L) (High 1.25x), Sodium (mmol/L) (Low 0.80x, high 1.15x), Multipliers are identified by "x", otherwise actual comparison values are provided with units. Values above and below this range were considered of PCI.
Time Frame	Up to Day 196

Outcome Measure Data

Analysis Population Description
mITT population. Only those participants with available data at the specified time points were analyzed (represented by n= X in the category titles)..

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	102	102	103	103	102	102
ALT, No change,n=99,102,102,102,101,100	99 97.1%	102 100%	101 98.1%	102 99%	101 99%	100 98%
ALT, High, n=99,102,102,102,101,100	0 0%	0 0%	1 1%	0 0%	0 0%	0 0%
ALP, No change,n=99,102,102,102,101,100	99 97.1%	102 100%	102 99%	102 99%	101 99%	100 98%
ALP, High, n=99,102,102,102,101,100	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
AST, No change,n=99,102,102,102,101,100	99 97.1%	102 100%	101 98.1%	102 99%	101 99%	100 98%
AST, High, n=99,102,102,102,101,100	0 0%	0 0%	1 1%	0 0%	0 0%	0 0%
Bilirubin, No change, n=99,102,102,102,101,100	99 97.1%	101 99%	102 99%	102 99%	101 99%	100 98%
Bilirubin, High, n=99, 102,102,102,101,100	0 0%	1 1%	0 0%	0 0%	0 0%	0 0%
Calcium, Low, n=96,102,101,101,101,99	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Calcium, No change, n=96,102,101,101,101,99	96 94.1%	102 100%	101 98.1%	101 98.1%	101 99%	99 97.1%
Calcium, High, n=96,102,101,101,101,99	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
CO2, Low, n=96,102,101,101,101,99	1 1%	0 0%	2 1.9%	1 1%	0 0%	1 1%
CO2, No change, n=96,102,101,101,101,99	94 92.2%	102 100%	99 96.1%	99 96.1%	101 99%	98 96.1%
CO2, High, n=96,102,101,101,101,99	1 1%	0 0%	0 0%	1 1%	0 0%	0 0%
Chloride, Low, n=96,102,101,101,101,99	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Chloride, No change, n=96,102,101,101,101,99	96 94.1%	102 100%	101 98.1%	101 98.1%	101 99%	99 97.1%
Chloride, High, n=96,102,101,101,101,99	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Creatinine, No change, n=96,102,101,101,101,99	94 92.2%	100 98%	99 96.1%	99 96.1%	99 97.1%	99 97.1%
Creatinine, High, n=96, 102, 101, 101, 101, 99	2 2%	2 2%	2 1.9%	2 1.9%	2 2%	0 0%
Direct bilirubin,NoChange,n=99,102,102,102,101,100	98 96.1%	102 100%	102 99%	102 99%	101 99%	100 98%
Direct bilirubin,High,n=99,102,102,102,101,100	1 1%	0 0%	0 0%	0 0%	0 0%	0 0%
Glucose, Low, n=96, 102, 101, 101, 101, 99	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Glucose, No change, n=96, 102, 101, 101, 101, 99	96 94.1%	102 100%	101 98.1%	101 98.1%	101 99%	99 97.1%
Glucose, High, n=96, 102, 101, 101, 101, 99	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Potassium, Low, n=96, 102, 101, 101, 101, 99	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Potassium, No change, n=96, 102, 101, 101, 101, 99	96 94.1%	102 100%	101 98.1%	101 98.1%	101 99%	99 97.1%
Potassium, High, n=96, 102, 101, 101, 101, 99	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Protein, No change, n=99, 102, 102, 102, 101, 100	99 97.1%	102 100%	102 99%	102 99%	101 99%	100 98%
Protein, High, n=99, 102, 102, 102, 101, 100	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Sodium, Low, n=96, 102, 101, 101, 101, 99	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Sodium, No change, n=96, 102, 101, 101, 101, 99	96 94.1%	102 100%	101 98.1%	101 98.1%	101 99%	99 97.1%
Sodium, High, n=96, 102, 101, 101, 101, 99	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Urea, Low, n=96, 102, 101, 101, 101, 99	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Urea, No change, n=96, 102, 101, 101, 101, 99	96 94.1%	101 99%	101 98.1%	100 97.1%	101 99%	98 96.1%
Urea, High, n=96, 102, 101, 101, 101, 99	0 0%	1 1%	0 0%	1 1%	0 0%	1 1%
Bilirubin/ALT,No change,n=99,102,102,102,101,100	99 97.1%	102 100%	102 99%	102 99%	101 99%	100 98%
Bilirubin/ALT, High,n=99,102,102,102,101,100	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%

8. Primary Outcome

Title	Number of Participants With Worst Case Vital Signs Parameter Results by PCI
Description	Vital signs parameters includes systolic blood pressure (SBP) and diastolic blood pressure (DBP), pulse rate and respiration rate were measured in a semi-supine position after 5 minutes rest for the participants at indicated time points. PCI ranges for vital signs parameters were as follows: <90 to >160 millimeters of mercury (mmHg) for SBP and <40 to >110 mmHg for DBP, <35 or >120 beats per minute for heart rate and <8 or >30 breaths per minute for respiration rate. Values above and below this range were considered of PCI.
Time Frame	Up to Day 168

Outcome Measure Data

Analysis Population Description
mITT population. Only those participants with available data at the specified time points were analyzed.

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	96	102	101	101	102	99
SBP, Low	0 0%	0 0%	0 0%	0 0%	0 0%	1 1%
SBP, No change	93 91.2%	92 90.2%	95 92.2%	98 95.1%	98 96.1%	94 92.2%
SBP, High	3 2.9%	10 9.8%	6 5.8%	3 2.9%	4 3.9%	4 3.9%
DBP, Low	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
DBP, No change	96 94.1%	102 100%	101 98.1%	101 98.1%	102 100%	99 97.1%
DBP, High	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Pulse rate, Low	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Pulse rate, No change	96 94.1%	102 100%	99 96.1%	100 97.1%	102 100%	98 96.1%
Pulse rate, High	0 0%	0 0%	2 1.9%	1 1%	0 0%	1 1%
Respiratory rate, Low	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Respiratory rate, No change	96 94.1%	102 100%	101 98.1%	101 98.1%	102 100%	98 96.1%
Respiratory rate, High	0 0%	0 0%	0 0%	0 0%	0 0%	1 1%

9. Primary Outcome

Title	Number of Participants With Worst Case Post-Baseline Abnormal 12-lead Electrocardiogram (ECG) Findings
Description	Triplicate 12-lead ECG obtained to measure PR, QRS, QT, and Corrected QT intervals. Only those participants with worst case post-Baseline data have been represented for abnormal - not clinical significant and abnormal - clinical significant. Day 1 was considered as Baseline.
Time Frame	Baseline and Day 168

Outcome Measure Data

Analysis Population Description
mITT population. Only those participants with available data at the specified time points were analyzed.

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	96	102	101	101	102	99
Not Clinical significant	52 51%	65 63.7%	68 66%	67 65%	62 60.8%	53 52%
Clinical significant	2 2%	1 1%	1 1%	0 0%	3 2.9%	1 1%

10. Secondary Outcome

Title	Number of Moderate or Severe Healthcare Resource Utilization (HCRU) Exacerbations Per Participant
Description	Participants with moderate or severe COPD exacerbations, i.e. breathlessness, cough, sputum production, chest congestion and chest tightness analyzed. Mild exacerbations are defined as exacerbations that did not require treatment with oral/systemic corticosteroids and/or antibiotics (not involving hospitalization, Emergency Room [ER] visit or resulting in death). Moderate exacerbations are defined as exacerbations that required treatment with oral/systemic corticosteroids and/or antibiotics (not involving hospitalization, ER visit or resulting in death). Severe exacerbations are defined as exacerbations that required hospitalization, ER visit or resulted in death. Number of moderate or severe HCRU exacerbations per participant has been presented, where 0= participants in each treatment group who did not experience an event; 1= participants in each treatment group who experienced 1 event and >=2= participants in each treatment group who experienced 2 or more events.
Time Frame	Up to Day 196

Outcome Measure Data

Analysis Population Description
Per Protocol Population.

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	101	102	100	103	100	99
0	66	51	61	63	55	50
1	28	34	23	28	30	36
>=2	7	17	16	12	15	13

11. Secondary Outcome

Title	Number of Responders E-RS in COPD (E-RS): COPD Total Score
Description	E-RS: COPD is a subset of EXACT. E-RS is a tool that consists of 11 items from the 14 item EXACT instrument. E-RS is intended to capture information related to the respiratory symptoms of COPD, i.e. breathlessness, cough, sputum production, chest congestion and chest tightness. The E-RS has a scoring range of 0-40; higher scores indicate more severe symptoms. Response is defined as an E-RS: COPD total score of 2 units below baseline or lower. Non-response is defined as an E-RS: COPD total score higher than 2 units below Baseline.
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description
Per Protocol Population. Number of participants presented represent those with data available at the time point being presented; however, all participants in the per protocol population without missing covariate information and with at least one post baseline measurement are included in the analysis.

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	86	95	87	91	85	86
Number [Participants]	33 32.4%	48 47.1%	33 32%	30 29.1%	29 28.4%	32 31.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 5 mg
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.089
	Comments	Analysis performed using a generalized linear mixed model with a logit link function including treatment, relevant Baseline E-RS: COPD score, smoking status at Screening, country, month, Baseline by month and treatment by month interactions.
	Method	linear mixed model
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.71
	Confidence Interval	(2-Sided) 90% 1.02 to 2.86
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds Ratio, 90% credible interval for Placebo and Danirixin 5 mg has been presented.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 10 mg
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.881
	Comments	Analysis performed using a generalized linear mixed model with a logit link function including treatment, relevant Baseline E-RS: COPD score, smoking status at Screening, country, month, Baseline by month and treatment by month interactions.
	Method	linear mixed model
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.05
	Confidence Interval	(2-Sided) 90% 0.62 to 1.79
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds Ratio, 90% credible interval for Placebo and Danirixin 10 mg has been presented.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 25 mg
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.674
	Comments	Analysis performed using a generalized linear mixed model with a logit link function including treatment, relevant Baseline E-RS: COPD score, smoking status at Screening, country, month, Baseline by month and treatment by month interactions.
	Method	linear mixed model
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 90% 0.51 to 1.48
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds Ratio, 90% credible interval for Placebo and Danirixin 25 mg has been presented.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 35 mg
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.804
	Comments	Analysis performed using a generalized linear mixed model with a logit link function including treatment, relevant Baseline E-RS: COPD score, smoking status at Screening, country, month, Baseline by month and treatment by month interactions.
	Method	linear mixed model
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.92
	Confidence Interval	(2-Sided) 90% 0.54 to 1.58
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds Ratio, 90% credible interval for Placebo and Danirixin 35 mg has been presented.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 50 mg
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.987
	Comments	Analysis performed using a generalized linear mixed model with a logit link function including treatment, relevant Baseline E-RS: COPD score, smoking status at Screening, country, month, Baseline by month and treatment by month interactions.
	Method	linear mixed model
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 90% 0.59 to 1.71
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds Ratio, 90% credible interval for Placebo and Danirixin 50 mg has been presented.

12. Secondary Outcome

Title	Number of EXACT Events Per Participant
Description	EXACT is a 14 item patient reported outcome (PRO) instrument designed to capture information on the occurrence, frequency, severity, and duration of exacerbations of disease in participants with COPD. The total score for EXACT-PRO ranges from 0-100, higher scores indicate more severe symptoms. Events were categorized as recovered, censored, or persistent worsening. Number of EXACT events per participant has been presented, where 0= participants in each treatment group who did not experience an event; 1= participants in each treatment group who experienced 1 event and >=2= participants in each treatment group who experienced 2 or more events.
Time Frame	Up to Day 196

Outcome Measure Data

Analysis Population Description
Per Protocol Population.

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	101	102	100	103	100	99
0	92	92	92	92	86	86
1	9	6	7	9	10	10
>=2	0	4	1	2	4	3

13. Secondary Outcome

Title	Time to First EXACT Event
Description	The time to first on-treatment EXACT event was calculated as the onset date of the first on-treatment EXACT event minus date of start of treatment plus 1.
Time Frame	Up to Day 168

Outcome Measure Data

Analysis Population Description
Per Protocol Population.

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	101	102	100	103	100	99
First quartile (Q1) time to event	NA	NA	NA	NA	NA	NA
Median time to event	NA	NA	NA	NA	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 5 mg
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Median Posterior Hazard Ratio
	Estimated Value	1.2
	Confidence Interval	(2-Sided) 90% 0.5 to 2.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Median Posterior Hazard Ratio, 90% credible interval for Placebo and Danirixin 5 mg has been presented.

Other Statistical Analysis		DNX versus (vs.) Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator % predicted Forced Expiratory Volume in one second (FEV1)at Screening.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 10 mg
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Median Posterior Hazard Ratio
	Estimated Value	1.0
	Confidence Interval	(2-Sided) 90% 0.4 to 2.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Median Posterior Hazard Ratio, 90% credible interval for Placebo and Danirixin 10 mg has been presented.

Other Statistical Analysis		DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator % predicted FEV1 at Screening.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 25 mg
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Median Posterior Hazard Ratio
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 90% 0.6 to 3.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Median Posterior Hazard Ratio, 90% credible interval for Placebo and Danirixin 25 mg has been presented.

Other Statistical Analysis		DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator % predicted FEV1 at Screening.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 35 mg
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Median Posterior Hazard Ratio
	Estimated Value	2.0
	Confidence Interval	(2-Sided) 90% 1.0 to 4.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Median Posterior Hazard Ratio, 90% credible interval for Placebo and Danirixin 35 mg has been presented.

Other Statistical Analysis		DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator % predicted FEV1 at Screening.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 50 mg
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Median Posterior Hazard Ratio
	Estimated Value	2.0
	Confidence Interval	(2-Sided) 90% 0.9 to 4.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Median Posterior Hazard Ratio, 90% credible interval for Placebo and Danirixin 50 mg has been presented.

Other Statistical Analysis		DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator % predicted FEV1 at Screening.

14. Secondary Outcome

Title	Severity of EXACT Event
Description	EXACT is a 14 item PRO instrument designed to capture information on the occurrence, frequency, severity, and duration of exacerbations of disease in participants with COPD. The total score for EXACT-PRO ranges from 0-100, higher scores indicate more severe symptoms. Severity is the highest EXACT total score during the period from onset to recovery.
Time Frame	Up to Day 168

Outcome Measure Data

Analysis Population Description
Per Protocol Population. Only those participants with data available at the specified data points were analyzed

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	9	15	9	13	19	16
Mean (Standard Deviation) [Scores on a scale]	22.1 (6.60)	26.7 (3.71)	22.9 (5.28)	28.6 (5.68)	25.0 (5.54)	26.4 (6.36)

15. Secondary Outcome

Title	EXACT Event Duration for All Events
Description	EXACT is a 14 item PRO instrument designed to capture information on the occurrence, frequency, severity, and duration of exacerbations of disease in participants with COPD. The total score for EXACT-PRO ranges from 0-100, higher scores indicate more severe symptoms. Severity is the highest EXACT total score during the period from onset to recovery. Duration of EXACT events has been reported.
Time Frame	Up to Day 168

Outcome Measure Data

Analysis Population Description
Per Protocol Population. Only those participants with data available at the specified data points were analyzed.

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	9	15	9	13	19	16
Mean (Standard Deviation) [Days]	45.3 (50.37)	11.6 (10.15)	45.8 (51.97)	25.5 (42.11)	17.6 (16.28)	18.7 (37.75)

16. Secondary Outcome

Title	Time to First HCRU-defined COPD Exacerbation
Description	The time to first on-treatment Moderate/Severe HCRU exacerbation was calculated as exacerbation onset date of first on-treatment moderate or severe on-treatment exacerbation - date of start of treatment +1.
Time Frame	Up to Day 196

Outcome Measure Data

Analysis Population Description
Per Protocol Population.

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	101	102	100	103	100	99
Q1 time to event	110	47	63	79	70	57
Median time to event	NA	NA	NA	NA	NA	152

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 5 mg
	Comments
	Type of Statistical Test	Other
	Comments	Bayesian proportional hazards model

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.5
	Confidence Interval	(2-Sided) 90% 1.0 to 2.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard Ratio, 90% credible interval for Placebo and Danirixin 5 mg has been presented.

Other Statistical Analysis		DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator %predicted FEV1 at Screening.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 10 mg
	Comments
	Type of Statistical Test	Other
	Comments	Bayesian proportional hazards model

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.1
	Confidence Interval	(2-Sided) 90% 0.8 to 1.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard Ratio, 90% credible interval for Placebo and Danirixin 10 mg has been presented.

Other Statistical Analysis		DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator % predicted FEV1 at Screening.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 25 mg
	Comments
	Type of Statistical Test	Other
	Comments	Bayesian proportional hazards model

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.1
	Confidence Interval	(2-Sided) 90% 0.7 to 1.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard Ratio, 90% credible interval for Placebo and Danirixin 25 mg has been presented.

Other Statistical Analysis		DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator % predicted FEV1 at Screening.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 35 mg
	Comments
	Type of Statistical Test	Other
	Comments	Bayesian proportional hazards model

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 90% 1.0 to 2.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard Ratio, 90% credible interval for Placebo and Danirixin 35 mg has been presented.

Other Statistical Analysis		DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator % predicted FEV1 at Screening.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 50 mg
	Comments
	Type of Statistical Test	Other
	Comments	Bayesian proportional hazards model

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.6
	Confidence Interval	(2-Sided) 90% 1.1 to 2.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard Ratio, 90% credible interval for Placebo and Danirixin 50 mg has been presented.

Other Statistical Analysis		DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator % predicted FEV1 at Screening.

17. Secondary Outcome

Title	Time to First Severe HCRU-defined COPD Exacerbation
Description	A COPD exacerbation defined as a severe exacerbation if it requires hospitalization or ER visit or extended observation. The time to first on-treatment Moderate/Severe HCRU exacerbation was calculated as exacerbation onset date of first on-treatment moderate or severe on-treatment exacerbation - date of start of treatment +1.
Time Frame	Up to Day 196

Outcome Measure Data

Analysis Population Description
Per Protocol Population.

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	101	102	100	103	100	99
Q1 time to event	NA	NA	NA	NA	NA	NA
Median time to event	NA	NA	NA	NA	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 5 mg
	Comments
	Type of Statistical Test	Other
	Comments	Bayesian proportional hazards model

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.8
	Confidence Interval	(2-Sided) 90% 0.7 to 5.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard Ratio, 90% credible interval for Placebo and Danirixin 5 mg has been presented.

Other Statistical Analysis		DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator % predicted FEV1 at Screening.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 10 mg
	Comments
	Type of Statistical Test	Other
	Comments	Bayesian proportional hazards model

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.9
	Confidence Interval	(2-Sided) 90% 0.7 to 5.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard Ratio, 90% credible interval for Placebo and Danirixin 10 mg has been presented.

Other Statistical Analysis		DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator % predicted FEV1 at Screening.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 25 mg
	Comments
	Type of Statistical Test	Other
	Comments	Bayesian proportional hazards model

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.8
	Confidence Interval	(2-Sided) 90% 0.7 to 5.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard Ratio, 90% credible interval for Placebo and Danirixin 25 mg has been presented.

Other Statistical Analysis		DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator % predicted FEV1 at Screening.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 35 mg
	Comments
	Type of Statistical Test	Other
	Comments	Bayesian proportional hazards model

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.3
	Confidence Interval	(2-Sided) 90% 0.9 to 6.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard Ratio, 90% credible interval for Placebo and Danirixin 35 mg has been presented.

Other Statistical Analysis		DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator % predicted FEV1 at Screening.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 50 mg
	Comments
	Type of Statistical Test	Other
	Comments	Bayesian proportional hazards model

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.8
	Confidence Interval	(2-Sided) 90% 0.2 to 2.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard Ratio, 90% credible interval for Placebo and Danirixin 50 mg has been presented.

Other Statistical Analysis		DNX vs. Placebo statistics calculated using a Bayesian proportional hazards model including treatment, gender, exacerbation history (<=1/>=2 moderate/severe), smoking status at Screening, country and post-bronchodilator % predicted FEV1 at Screening.

18. Secondary Outcome

Title	HCRU-defined Exacerbation Duration
Description	The duration of HCRU exacerbation were determined. The duration of the exacerbation was calculated as (exacerbation resolution date or date of death - exacerbation onset date + 1). For exacerbations which were not resolved but where the participant later died from other causes, the duration was calculated using date of death as the end date of the event.
Time Frame	Up to Day 196

Outcome Measure Data

Analysis Population Description
Per Protocol Population. Only those participants with data available at the specified data points were analyzed.

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	44	75	58	56	66	65
Mean (Standard Deviation) [Days]	10.3 (7.37)	12.3 (8.95)	12.9 (9.58)	14.0 (8.71)	10.7 (7.21)	14.2 (9.29)

19. Secondary Outcome

Title	Change From Baseline in St. George's Respiratory Questionnaire for COPD Patients (SGRQ-C) Total Score
Description	The SGRQ-C consists of 40 items aggregated into 3 component scores: Symptoms, Activity, Impacts, and a Total score. Each response to a question is assigned a weight. Component scores are calculated by summing the weights from all positive items in that component, dividing by the sum of weights for all items in that component, and multiplying this number by 100. Component scores could range from 0-100, with a higher component score indicating greater disease burden. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Posterior mean change and standard deviation has been presented.
Time Frame	Baseline, Days 84 and 168

Outcome Measure Data

Analysis Population Description
Per Protocol Population. Number of participants presented represent those with data available at the time point being presented; however, all participants in the per protocol population without missing covariate information and with at least one post baseline measurement are included in the analysis.

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	101	102	100	103	100	99
Day 84, n=93, 97, 94, 96, 91, 90	-3.79 (1.172)	-3.63 (1.150)	-1.31 (1.146)	-3.19 (1.148)	-2.83 (1.189)	-2.48 (1.175)
Day 168, n=85, 96, 86, 90, 86, 85	-4.11 (1.292)	-3.44 (1.246)	-4.19 (1.292)	-4.94 (1.251)	-4.12 (1.287)	-3.41 (1.302)

20. Secondary Outcome

Title	Number of SGRQ Responder
Description	A participant was consider Responder according to SGRQ total score if their change from Baseline SGRQ total score of 4 units below Baseline or lower.
Time Frame	Day 84 and Day 168

Outcome Measure Data

Analysis Population Description
Per Protocol Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	101	102	100	103	100	99
Day 84, n=93, 97, 94, 96, 91, 90	39 38.2%	40 39.2%	35 34%	49 47.6%	35 34.3%	38 37.3%
Day 168, n=85, 96, 86, 90, 86, 85	35 34.3%	47 46.1%	40 38.8%	47 45.6%	41 40.2%	34 33.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 5 mg
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.208
	Comments	Analysis performed using a generalized linear mixed model with a logit link function including treatment, Baseline SGRQ total score, smoking status at Screening, country, visit, Baseline by visit and treatment by visit interactions.
	Method	Linear mixed model
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.51
	Confidence Interval	(2-Sided) 90% 0.88 to 2.59
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds Ratio, 90% credible interval for Placebo and Danirixin 5 mg has been presented.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 10 mg
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.482
	Comments	Analysis performed using a generalized linear mixed model with a logit link function including treatment, Baseline SGRQ total score, smoking status at Screening, country, visit, Baseline by visit and treatment by visit interactions.
	Method	Linear mixed model
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.27
	Confidence Interval	(2-Sided) 90% 0.73 to 2.20
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds Ratio, 90% credible interval for Placebo and Danirixin 10 mg has been presented.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 25 mg
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.239
	Comments	Analysis performed using a generalized linear mixed model with a logit link function including treatment, Baseline SGRQ total score, smoking status at Screening, country, visit, Baseline by visit and treatment by visit interactions.
	Method	Linear mixed model
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.47
	Confidence Interval	(2-Sided) 90% 0.86 to 2.53
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds Ratio, 90% credible interval for Placebo and Danirixin 25 mg has been presented.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 35 mg
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.426
	Comments	Analysis performed using a generalized linear mixed model with a logit link function including treatment, Baseline SGRQ total score, smoking status at Screening, country, visit, Baseline by visit and treatment by visit interactions.
	Method	Linear mixed model
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.31
	Confidence Interval	(2-Sided) 90% 0.75 to 2.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds Ratio, 90% credible interval for Placebo and Danirixin 35 mg has been presented.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 50 mg
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.763
	Comments	Analysis performed using a generalized linear mixed model with a logit link function including treatment, Baseline SGRQ total score, smoking status at Screening, country, visit, Baseline by visit and treatment by visit interactions.
	Method	Linear mixed model
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 90% 0.52 to 1.58
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds Ratio, 90% credible interval for Placebo and Danirixin 50 mg has been presented.

21. Secondary Outcome

Title	Change From Baseline COPD Assessment Test (CAT) Total Score
Description	The CAT is an 8 item questionnaire (cough, sputum, chest tightness, breathlessness, going up hills/stairs, activity limitation at home, confidence leaving the home, and sleep and energy) that measures health status of participants with COPD. Participants were completed each question by rating their experience on a 6 point scale ranging from 0 (maximum impairment) to 5 (no impairment) with a total scoring range of 0-40; higher scores indicate worse health status. A CAT score was calculated by summing the non-missing scores on the eight items. Individual items are scored from 0 to 5 with a total score range from 0 - 40, higher scores indicate greater disease impact. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Posterior mean change and standard deviation has been presented.
Time Frame	Baseline, Days 84 and 168

Outcome Measure Data

Analysis Population Description
Per Protocol Population. Number of participants presented represent those with data available at the time point being presented; however, all participants in the per protocol population without missing covariate information and with at least one post baseline measurement are included in the analysis.

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	101	102	100	103	100	99
Day 84, n=89, 97, 92, 89, 88, 85	-2.02 (0.536)	-0.86 (0.525)	-0.63 (0.524)	-0.55 (0.542)	-1.51 (0.543)	-0.36 (0.549)
Day 168, n=84, 94, 86, 87, 85, 83	-1.39 (0.557)	-1.39 (0.537)	-1.23 (0.548)	-0.97 (0.560)	-1.56 (0.560)	-1.32 (0.565)

22. Secondary Outcome

Title	Number of CAT Responder
Description	A participant was considered as a responder according to CAT score if their change from Baseline CAT score 2.0 units below Baseline or lower.
Time Frame	Day 84 and Day 168

Outcome Measure Data

Analysis Population Description
Per Protocol Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	101	102	100	103	100	99
Day 84, n=89, 97, 92, 89, 88, 85	46 45.1%	44 43.1%	38 36.9%	37 35.9%	43 42.2%	36 35.3%
Day 168, n=84, 94, 86, 87, 85, 83	41 40.2%	44 43.1%	39 37.9%	42 40.8%	46 45.1%	44 43.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 5 mg
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.973
	Comments	Analysis performed using a generalized linear mixed model with a logit link function including treatment, Baseline CAT score, smoking status at Screening, country, visit, Baseline by visit and treatment by visit interactions.
	Method	Linear mixed model
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 90% 0.58 to 1.76
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds Ratio, 90% credible interval for Placebo and Danirixin 5 mg has been presented.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 10 mg
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.825
	Comments	Analysis performed using a generalized linear mixed model with a logit link function including treatment, Baseline CAT score, smoking status at Screening, country, visit, Baseline by visit and treatment by visit interactions.
	Method	Linear mixed model
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 90% 0.53 to 1.63
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds Ratio, 90% credible interval for Placebo and Danirixin 10 mg has been presented.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 25 mg
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.887
	Comments	Analysis performed using a generalized linear mixed model with a logit link function including treatment, Baseline CAT score, smoking status at Screening, country, visit, Baseline by visit and treatment by visit interactions.
	Method	Linear mixed model
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.95
	Confidence Interval	(2-Sided) 90% 0.55 to 1.66
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds Ratio, 90% credible interval for Placebo and Danirixin 25 mg has been presented.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 35 mg
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.567
	Comments	Analysis performed using a generalized linear mixed model with a logit link function including treatment, Baseline CAT score, smoking status at Screening, country, visit, Baseline by visit and treatment by visit interactions.
	Method	Linear mixed model
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.21
	Confidence Interval	(2-Sided) 90% 0.69 to 2.13
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds Ratio, 90% credible interval for Placebo and Danirixin 35 mg has been presented.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo, Danirixin 50 mg
	Comments
	Type of Statistical Test	Other
	Comments

Statistical Test of Hypothesis	p-Value	0.501
	Comments	Analysis performed using a generalized linear mixed model with a logit link function including treatment, Baseline CAT score, smoking status at Screening, country, visit, Baseline by visit and treatment by visit interactions.
	Method	Linear mixed model
	Comments

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.26
	Confidence Interval	(2-Sided) 90% 0.72 to 2.20
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds Ratio, 90% credible interval for Placebo and Danirixin 50 mg has been presented.

23. Secondary Outcome

Title	Change From Baseline in Post-bronchodilator FEV1 as a Lung Function Assessment
Description	Spirometric analysis was done to determine FEV1. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Least square mean change from Baseline and standard error has been presented.
Time Frame	Baseline, Days 84 and 168

Outcome Measure Data

Analysis Population Description
mITT Population. Number of participants presented represent those with data available at the time point being presented; however, all participants in the mITT population without missing covariate information and with at least one post baseline measurement are included in the analysis.

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	102	102	103	103	102	102
Day 84, n=94, 99, 98, 97, 92, 93	0.016 (0.0208)	-0.031 (0.0203)	-0.029 (0.0204)	-0.018 (0.0206)	-0.027 (0.0211)	0.027 (0.0210)
Day 168, n=88, 97, 90, 90, 88, 86	-0.016 (0.0199)	-0.043 (0.0191)	-0.033 (0.0197)	-0.058 (0.0198)	-0.012 (0.0201)	-0.011 (0.0202)

24. Secondary Outcome

Title	Percent Predicted Normal FEV1
Description	Spirometric analysis was done to determine percent predicted FEVI at screening. FEV1 is forced expiratory volume in one second. Percent predicted FEV1 is defined as the percent FEV1 of the participant is divided by average FEV1 percent in the population of any person similar age, sex and body composition.
Time Frame	At Screening

Outcome Measure Data

Analysis Population Description
Per Protocol Population. Only those participants with available data at the specified time points were analyzed.

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	100	102	100	103	100	99
Mean (Standard Deviation) [Percent predicted FEV1]	58.98 (12.838)	56.75 (12.038)	56.62 (11.848)	56.84 (12.813)	57.51 (14.076)	57.84 (12.794)

25. Secondary Outcome

Title	Change From Baseline in Post-bronchodilator Forced Vital Capacity (FVC) as a Lung Function Assessment
Description	Spirometric analysis was done to determine FVC. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Least square mean change from Baseline and standard error has been presented.
Time Frame	Baseline, Days 84 and 168

Outcome Measure Data

Analysis Population Description
mITT Population. Number of participants presented represent those with data available at the time point being presented; however, all participants in the mITT population without missing covariate information and with at least one post baseline measurement are included in the analysis.

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	102	102	103	103	102	102
Day 84, n=94, 99, 98, 97, 92, 93	0.024 (0.0321)	-0.054 (0.0313)	-0.043 (0.0315)	0.027 (0.0317)	-0.049 (0.0326)	0.014 (0.0323)
Day 168, n=88, 97, 90, 90, 88, 86	-0.011 (0.0348)	-0.079 (0.0335)	-0.043 (0.0344)	-0.024 (0.0345)	-0.036 (0.0351)	-0.016 (0.0353)

26. Secondary Outcome

Title	Change From Baseline in Post-bronchodilator FEV1/FVC Ratio as a Lung Function Assessment
Description	Spirometric analysis was done to determine FEV1 and FVC. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value.
Time Frame	Baseline, Days 84 and 168

Outcome Measure Data

Analysis Population Description
mITT Population. Number of participants presented represent those with data available at the time point being presented; however, all participants in the mITT population without missing covariate information and with at least one post baseline measurement are included in the analysis.

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	102	102	103	103	102	102
Day 84, n=94, 99, 98, 97, 92, 93	-0.003 (0.0543)	-0.001 (0.0554)	-0.000 (0.0453)	-0.013 (0.0630)	-0.000 (0.0402)	0.014 (0.1636)
Day 168, n=88, 97, 90, 90, 88, 86	-0.007 (0.0622)	-0.003 (0.0555)	0.003 (0.0420)	-0.015 (0.0610)	0.002 (0.0495)	-0.002 (0.0385)

27. Secondary Outcome

Title	Change From Baseline Number of Puffs of Rescue Medication Per Day
Description	The mean number of puffs of rescue per day was calculated over the same time periods and using the same assumptions as rescue use via diary. Day 1 was considered as Baseline. Change from Baseline was calculated by subtracting Baseline value from the specified time point value. Least square mean change from Baseline and standard error has been presented.
Time Frame	Baseline, Months 1, 2, 3, 4, 5 and 6

Outcome Measure Data

Analysis Population Description
Per Protocol Population. Number of participants presented represent those with data available at the time point being presented; however, all participants in the per protocol population without missing covariate information and with at least one post Baseline measurement are included in the analysis.

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	101	102	100	103	100	99
Month 1, n=100, 102, 100, 102, 98, 99	0.00 (0.132)	0.36 (0.130)	0.28 (0.132)	0.15 (0.130)	-0.03 (0.133)	0.28 (0.133)
Month 2, n=96, 100, 98, 97, 98, 96	-0.22 (0.187)	0.42 (0.184)	0.18 (0.186)	0.35 (0.185)	0.07 (0.187)	0.33 (0.188)
Month 3, n=95, 100, 95, 97, 94, 92	-0.18 (0.184)	0.29 (0.181)	0.21 (0.184)	0.25 (0.182)	0.07 (0.185)	0.27 (0.186)
Month 4, n=92, 98, 92, 97, 90, 90	-0.18 (0.193)	0.27 (0.189)	0.27 (0.192)	0.21 (0.190)	-0.04 (0.194)	0.44 (0.195)
Month 5, n=88, 97, 88, 94, 87, 87	-0.16 (0.190)	0.17 (0.186)	0.19 (0.190)	0.25 (0.187)	-0.06 (0.191)	0.29 (0.192)
Month 6, n=86, 95, 88, 91, 85, 86	-0.17 (0.196)	0.21 (0.191)	0.10 (0.195)	0.15 (0.193)	0.04 (0.197)	0.28 (0.198)

28. Secondary Outcome

Title	Participant Experience of Physical Activity Measured Using PROactive Physical Activity in COPD (C-PPAC) Questionnaire
Description	The Clinical Visit PROactive Physical Activity in COPD (C-PPAC) tool is a designed for intermittent use within a clinical study. PROactive Total Score and two domain scores (amount and difficulty) are derived using data from the C-PPAC questionnaire and a physical activity monitor worn for 7 days prior to the questionnaire.C-PPAC is a 12 item questionnaire. The PROactive tools are scored from 0 to 100 with higher scores indicating greater disease impact. It was implemented in a subset of approximately 50% of participants. The amount domain is calculated using 2 items from the C-PPAC questionnaire (amount of walking outside and chores outside) and 2 activity monitor outputs (vector magnitude units per minute (VMU/min) and steps/day). Each domain score is based on the addition of items (0-15 for amount and 0-40 for difficulty) and then scaled from 0-100. The total score is calculated as (amount+difficulty)/2.
Time Frame	Days 84 and 168

Outcome Measure Data

Analysis Population Description
Per Protocol Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Placebo	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	101	102	100	103	100	99
Total score, Day 84, n=8, 4, 6, 6, 10, 6	3.00 (5.964)	-5.75 (6.035)	-3.83 (12.754)	0.42 (2.635)	-1.20 (8.453)	2.33 (2.677)
Total score, Day 168, n=13, 7, 9, 8, 6, 7	-0.96 (13.266)	1.86 (9.344)	2.11 (5.878)	1.25 (3.423)	4.08 (6.492)	0.43 (7.607)
Amount score, Day 84, n=8, 4, 6, 6, 10, 6	2.25 (5.825)	-8.50 (7.937)	-4.00 (19.204)	0.00 (6.957)	-4.20 (10.706)	-0.83 (5.345)
Amount score, Day 168, n=13, 7, 9, 8, 6, 7	-3.69 (14.733)	-0.43 (8.810)	2.11 (9.558)	1.25 (9.161)	3.67 (11.708)	-4.14 (12.522)
Difficult score, Day 84, n=29, 22, 18, 19, 24, 14	6.38 (9.511)	1.64 (8.301)	-0.17 (7.679)	1.89 (11.704)	2.79 (9.278)	4.50 (9.598)
Difficult score, Day 168, n=29, 20, 18, 19, 25, 15	3.03 (14.409)	2.20 (11.039)	2.11 (7.553)	0.63 (11.413)	1.52 (9.687)	4.87 (8.887)

29. Secondary Outcome

Title	Danirixin Whole Blood Pharmacokinetic Concentration-Time Data
Description	Blood samples were collected from the participants for the analysis of blood pharmacokinetic concentration-time data. All participants in the mITT population who had at least 1 non-missing Pharmacokinetic assessment obtained and analyzed whilst on treatment with danirixin were included Pharmacokinetic population.
Time Frame	Pre-dose on Days 1, 56, 84 and 168; 0.5, 1, 2, 4, 6, 8, 10, 12 hours post-dose on Days 1 and 168

Outcome Measure Data

Analysis Population Description
Pharmacokinetic Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	102	103	102	102	101
Day 1, Pre-dose, n=97, 99, 102, 102, 100	2.1 (19.41)	0.4 (3.92)	0.3 (3.06)	17.2 (169.33)	3.9 (39.10)
Day 1, 0.5 hour, n=16, 19, 24, 26, 19	86.7 (85.73)	210.4 (207.54)	730.5 (1046.42)	976.1 (839.37)	1331.0 (1220.06)
Day 1, 1 hour, n=16, 18, 24, 26, 19	148.3 (104.75)	343.3 (228.66)	822.0 (527.47)	1183.5 (760.02)	1846.2 (979.95)
Day 1, 2 hours, n=16, 19, 24, 26, 19	115.3 (46.00)	277.7 (245.32)	707.7 (256.63)	1011.2 (398.82)	1472.8 (858.49)
Day 1, 4 hours, n=16, 19, 24, 26, 19	59.2 (17.79)	165.3 (136.50)	401.5 (188.75)	591.5 (302.96)	904.6 (599.85)
Day 1, 6 hours, n=16, 19, 24, 26, 19	34.4 (12.32)	100.6 (84.26)	270.0 (169.37)	371.5 (335.23)	594.9 (525.00)
Day 1, 8 hours, n=15, 19, 24, 26, 19	26.1 (13.54)	67.8 (61.02)	213.8 (162.24)	325.8 (359.79)	428.2 (398.16)
Day 1, 10 hours, n=16, 18, 22, 26, 19	42.5 (67.85)	61.5 (56.67)	265.0 (396.25)	274.5 (328.04)	302.3 (255.81)
Day 1, 12 hours, n=16, 16, 21, 26, 18	87.2 (174.14)	74.7 (82.51)	188.2 (188.27)	232.8 (316.67)	459.3 (561.53)
Day 56, Pre-dose, n=94, 91, 94, 95, 92	53.2 (73.19)	91.8 (102.43)	252.3 (295.15)	372.1 (427.41)	572.0 (738.28)
Day 84, Pre-dose, n=97, 94, 96, 91, 90	50.2 (77.78)	76.2 (106.86)	212.3 (211.35)	342.8 (411.28)	484.3 (527.47)
Day 168, Pre-dose, n=92, 85, 89, 85, 84	41.2 (38.02)	99.5 (138.00)	217.9 (221.92)	350.7 (336.07)	459.5 (421.30)
Day 168, 0.5 hours, n=14, 12, 17, 18, 16	147.7 (91.51)	248.3 (189.30)	530.5 (536.75)	1449.5 (949.00)	1635.6 (1077.48)
Day 168, 1 hours, n=14, 13, 17, 18, 16	162.1 (108.88)	314.0 (157.04)	681.2 (630.86)	1590.3 (1019.32)	1725.4 (870.79)
Day 168, 2 hours, n=14, 13, 17, 18, 16	127.4 (88.80)	331.9 (164.10)	574.7 (445.85)	1045.2 (414.21)	1736.6 (592.51)
Day 168, 4 hours, n=13, 11, 16, 18, 16	90.5 (53.67)	190.9 (103.35)	452.8 (289.44)	805.0 (346.87)	1459.9 (909.32)
Day 168, 6 hours, n=13, 13, 16, 18, 15	55.6 (26.36)	135.5 (87.39)	289.6 (188.04)	554.8 (313.52)	960.4 (633.37)
Day 168, 8 hours, n=13, 13, 17, 18, 15	41.5 (19.75)	102.6 (60.14)	245.1 (165.40)	444.9 (298.69)	760.8 (679.30)
Day 168, 10 hours, n=13, 12, 17, 18, 15	42.4 (35.98)	76.6 (56.95)	193.9 (128.42)	380.2 (285.81)	715.0 (840.54)
Day 168, 12 hours, n=13, 12, 17, 18, 15	42.2 (41.29)	73.1 (41.21)	169.7 (114.20)	481.2 (640.17)	662.4 (877.91)

30. Secondary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time Zero to Last Time of Quantifiable Concentration [AUC(0-t)] of Danirixin in Whole Blood Using Dried Blood Spot
Description	Blood samples were collected at indicated timepoints for the analysis of phamacokinetic parameter. All participants in the PK population who had at least 1 non-missing PK assessment obtained and analyzed whilst on treatment with danirixin from a dry blood spot sample and corresponding wet whole blood sample were included in Pharmacokinetic population.
Time Frame	Days 1 and 168

Outcome Measure Data

Analysis Population Description
Pharmacokinetic Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	102	103	102	102	101
Day 1, n=17, 19, 24, 26, 19	543.0	1373.1	3851.5	5485.1	8073.4
Day 168, n=14, 13, 17, 18, 16	752.1	1701.8	4170.1	7682.6	11538.0

31. Secondary Outcome

Title	Concentration Maximum (Cmax) of Danirixin in Whole Blood Using Dried Blood Spots
Description	Blood samples were collected from the participants for the analysis of pharmacokinetic parameter.
Time Frame	Days 1 and 168

Outcome Measure Data

Analysis Population Description
Pharmacokinetic Population. Only those participants with data available at the specified data points were analyzed (represented by n= X in the category titles).

Arm/Group Title	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	102	103	102	102	101
Day 1, n=17, 19, 24, 26, 19	164.9	343.1	1028.8	1386.2	2119.1
Day 168, n=14, 13, 17, 18, 16	171.9	357.3	821.2	1695.0	2390.5

32. Secondary Outcome

Title	Time to Reach Maximum Plasma Concentration (Tmax) of Danirixin in Whole Blood Using Dried Blood Spots
Description	Blood samples were collected from the participants for the analysis of pharmacokinetic parameter.
Time Frame	Days 1 and 168

Outcome Measure Data

Analysis Population Description
Pharmacokinetic Population.

Arm/Group Title	Danirixin 5 mg	Danirixin 10 mg	Danirixin 25 mg	Danirixin 35 mg	Danirixin 50 mg
Arm/Group Description	Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.	Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
Measure Participants	102	103	102	102	101
Day 1, n=17, 19, 24, 26, 19	1.000	1.000	1.000	1.000	1.000
Day 168, n=14, 13, 17, 18, 16	1.000	1.000	1.000	1.000	1.542

Adverse Events

	Placebo		Danirixin 5 mg		Danirixin 10 mg		Danirixin 25 mg		Danirixin 35 mg		Danirixin 50 mg
Time Frame	On-treatment serious adverse events (SAEs) and non serious AEs were collected from the start of study treatment up to 196 days
Adverse Event Reporting Description	mITT population comprised of all randomized participants who were randomized apart from those randomized in error, received a treatment randomization number, modified and data for this population were based on actual treatment received. SAEs and AEs were reported for mITT Population.

Arm/Group Title	Placebo		Danirixin 5 mg		Danirixin 10 mg		Danirixin 25 mg		Danirixin 35 mg		Danirixin 50 mg
Arm/Group Description	Participants received placebo film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.		Participants received danirixin 5 milligram (mg) film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.		Participants received danirixin 10 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.		Participants received danirixin 25 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.		Participants received danirixin 35 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.		Participants received danirixin 50 mg film coated tablets orally twice daily with food and standard care of treatment for 24 weeks.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/102 (0%)		0/102 (0%)		1/103 (1%)		2/103 (1.9%)		1/102 (1%)		1/102 (1%)
Serious Adverse Events
	Placebo		Danirixin 5 mg		Danirixin 10 mg		Danirixin 25 mg		Danirixin 35 mg		Danirixin 50 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/102 (7.8%)		7/102 (6.9%)		13/103 (12.6%)		10/103 (9.7%)		7/102 (6.9%)		11/102 (10.8%)
Blood and lymphatic system disorders
Anaemia	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	1/103 (1%)	1	0/102 (0%)	0	0/102 (0%)	0
Lymphadenopathy	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	1/103 (1%)	1	0/102 (0%)	0	0/102 (0%)	0
Cardiac disorders
Atrial fibrillation	0/102 (0%)	0	1/102 (1%)	2	2/103 (1.9%)	2	0/103 (0%)	0	0/102 (0%)	0	0/102 (0%)	0
Angina pectoris	1/102 (1%)	1	1/102 (1%)	1	0/103 (0%)	0	0/103 (0%)	0	0/102 (0%)	0	0/102 (0%)	0
Coronary artery disease	0/102 (0%)	0	0/102 (0%)	0	1/103 (1%)	1	0/103 (0%)	0	0/102 (0%)	0	0/102 (0%)	0
Ischaemic cardiomyopathy	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	0/103 (0%)	0	1/102 (1%)	1	0/102 (0%)	0
Mitral valve incompetence	0/102 (0%)	0	1/102 (1%)	1	0/103 (0%)	0	0/103 (0%)	0	0/102 (0%)	0	0/102 (0%)	0
Myocardial infarction	0/102 (0%)	0	1/102 (1%)	1	0/103 (0%)	0	0/103 (0%)	0	0/102 (0%)	0	0/102 (0%)	0
Ear and labyrinth disorders
Vertigo	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	1/103 (1%)	1	0/102 (0%)	0	0/102 (0%)	0
Gastrointestinal disorders
Anal prolapse	0/102 (0%)	0	0/102 (0%)	0	1/103 (1%)	1	0/103 (0%)	0	0/102 (0%)	0	0/102 (0%)	0
Chronic gastritis	1/102 (1%)	1	0/102 (0%)	0	0/103 (0%)	0	0/103 (0%)	0	0/102 (0%)	0	0/102 (0%)	0
Faecaloma	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	1/103 (1%)	1	0/102 (0%)	0	0/102 (0%)	0
Gastrointestinal perforation	0/102 (0%)	0	1/102 (1%)	1	0/103 (0%)	0	0/103 (0%)	0	0/102 (0%)	0	0/102 (0%)	0
Gastrooesophageal reflux disease	0/102 (0%)	0	0/102 (0%)	0	1/103 (1%)	1	0/103 (0%)	0	0/102 (0%)	0	0/102 (0%)	0
Haemorrhoids	0/102 (0%)	0	0/102 (0%)	0	1/103 (1%)	1	0/103 (0%)	0	0/102 (0%)	0	0/102 (0%)	0
Large intestine perforation	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	1/103 (1%)	1	0/102 (0%)	0	0/102 (0%)	0
Large intestine polyp	1/102 (1%)	1	0/102 (0%)	0	0/103 (0%)	0	0/103 (0%)	0	0/102 (0%)	0	0/102 (0%)	0
Lower gastrointestinal haemorrhage	0/102 (0%)	0	0/102 (0%)	0	1/103 (1%)	1	0/103 (0%)	0	0/102 (0%)	0	0/102 (0%)	0
Pancreatitis	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	0/103 (0%)	0	1/102 (1%)	1	0/102 (0%)	0
Pancreatitis chronic	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	1/103 (1%)	1	0/102 (0%)	0	0/102 (0%)	0
Small intestinal obstruction	0/102 (0%)	0	0/102 (0%)	0	1/103 (1%)	1	0/103 (0%)	0	0/102 (0%)	0	0/102 (0%)	0
General disorders
Death	0/102 (0%)	0	0/102 (0%)	0	1/103 (1%)	1	2/103 (1.9%)	2	0/102 (0%)	0	0/102 (0%)	0
Sudden death	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	0/103 (0%)	0	1/102 (1%)	1	0/102 (0%)	0
Hepatobiliary disorders
Hepatic cyst	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	0/103 (0%)	0	0/102 (0%)	0	1/102 (1%)	1
Hepatic steatosis	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	1/103 (1%)	1	0/102 (0%)	0	0/102 (0%)	0
Infections and infestations
Pneumonia	0/102 (0%)	0	0/102 (0%)	0	2/103 (1.9%)	2	1/103 (1%)	1	1/102 (1%)	1	4/102 (3.9%)	4
Arthritis bacterial	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	0/103 (0%)	0	0/102 (0%)	0	1/102 (1%)	1
Metapneumovirus infection	0/102 (0%)	0	1/102 (1%)	1	0/103 (0%)	0	0/103 (0%)	0	0/102 (0%)	0	0/102 (0%)	0
Perichondritis	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	0/103 (0%)	0	0/102 (0%)	0	1/102 (1%)	1
Pilonidal cyst	0/102 (0%)	0	0/102 (0%)	0	1/103 (1%)	1	0/103 (0%)	0	0/102 (0%)	0	0/102 (0%)	0
Psoas abscess	0/102 (0%)	0	1/102 (1%)	1	0/103 (0%)	0	0/103 (0%)	0	0/102 (0%)	0	0/102 (0%)	0
Pyelonephritis acute	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	0/103 (0%)	0	0/102 (0%)	0	1/102 (1%)	1
Septic shock	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	0/103 (0%)	0	0/102 (0%)	0	1/102 (1%)	1
Injury, poisoning and procedural complications
Facial bones fracture	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	0/103 (0%)	0	0/102 (0%)	0	1/102 (1%)	1
Metabolism and nutrition disorders
Decreased appetite	1/102 (1%)	1	0/102 (0%)	0	0/103 (0%)	0	0/103 (0%)	0	0/102 (0%)	0	0/102 (0%)	0
Diabetes mellitus	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	1/103 (1%)	1	0/102 (0%)	0	0/102 (0%)	0
Musculoskeletal and connective tissue disorders
Osteoarthritis	1/102 (1%)	1	0/102 (0%)	0	1/103 (1%)	1	1/103 (1%)	1	0/102 (0%)	0	0/102 (0%)	0
Ankylosing spondylitis	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	0/103 (0%)	0	0/102 (0%)	0	1/102 (1%)	1
Musculoskeletal chest pain	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	0/103 (0%)	0	0/102 (0%)	0	1/102 (1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer	0/102 (0%)	0	1/102 (1%)	1	1/103 (1%)	1	0/103 (0%)	0	0/102 (0%)	0	0/102 (0%)	0
Lung neoplasm malignant	0/102 (0%)	0	0/102 (0%)	0	1/103 (1%)	1	1/103 (1%)	2	0/102 (0%)	0	0/102 (0%)	0
Bladder papilloma	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	0/103 (0%)	0	0/102 (0%)	0	1/102 (1%)	1
Cardiac neoplasm unspecified	1/102 (1%)	1	0/102 (0%)	0	0/103 (0%)	0	0/103 (0%)	0	0/102 (0%)	0	0/102 (0%)	0
Oesophageal adenocarcinoma	1/102 (1%)	1	0/102 (0%)	0	0/103 (0%)	0	0/103 (0%)	0	0/102 (0%)	0	0/102 (0%)	0
Prostate cancer	1/102 (1%)	1	0/102 (0%)	0	0/103 (0%)	0	0/103 (0%)	0	0/102 (0%)	0	0/102 (0%)	0
Squamous cell carcinoma	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	0/103 (0%)	0	1/102 (1%)	1	0/102 (0%)	0
Nervous system disorders
Diabetic neuropathy	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	1/103 (1%)	1	0/102 (0%)	0	0/102 (0%)	0
Hemiparesis	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	0/103 (0%)	0	0/102 (0%)	0	1/102 (1%)	1
Sciatica	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	0/103 (0%)	0	0/102 (0%)	0	1/102 (1%)	1
Renal and urinary disorders
Haematuria	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	0/103 (0%)	0	0/102 (0%)	0	1/102 (1%)	1
Respiratory, thoracic and mediastinal disorders
Epistaxis	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	0/103 (0%)	0	0/102 (0%)	0	1/102 (1%)	1
Chronic obstructive pulmonary disease	1/102 (1%)	1	1/102 (1%)	1	1/103 (1%)	1	2/103 (1.9%)	2	2/102 (2%)	2	0/102 (0%)	0
Haemoptysis	0/102 (0%)	0	0/102 (0%)	0	1/103 (1%)	1	0/103 (0%)	0	0/102 (0%)	0	0/102 (0%)	0
Pulmonary embolism	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	1/103 (1%)	1	0/102 (0%)	0	0/102 (0%)	0
Vascular disorders
Deep vein thrombosis	0/102 (0%)	0	0/102 (0%)	0	0/103 (0%)	0	1/103 (1%)	1	0/102 (0%)	0	0/102 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Danirixin 5 mg		Danirixin 10 mg		Danirixin 25 mg		Danirixin 35 mg		Danirixin 50 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/102 (19.6%)		24/102 (23.5%)		22/103 (21.4%)		31/103 (30.1%)		27/102 (26.5%)		27/102 (26.5%)
Infections and infestations
Nasopharyngitis	12/102 (11.8%)	13	8/102 (7.8%)	8	9/103 (8.7%)	11	12/103 (11.7%)	14	14/102 (13.7%)	16	10/102 (9.8%)	14
Upper respiratory tract infection	5/102 (4.9%)	6	7/102 (6.9%)	7	7/103 (6.8%)	8	9/103 (8.7%)	12	5/102 (4.9%)	8	6/102 (5.9%)	8
Musculoskeletal and connective tissue disorders
Back pain	4/102 (3.9%)	4	7/102 (6.9%)	7	4/103 (3.9%)	4	6/103 (5.8%)	7	5/102 (4.9%)	6	5/102 (4.9%)	5
Nervous system disorders
Headache	2/102 (2%)	2	4/102 (3.9%)	4	6/103 (5.8%)	6	5/103 (4.9%)	8	8/102 (7.8%)	9	8/102 (7.8%)	8

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.

Results Point of Contact

Name/Title	GSK Response Center
Organization	GlaxoSmithKline
Phone	866-435-7343
Email	GSKClinicalSupportHD@gsk.com

Responsible Party:

GlaxoSmithKline

ClinicalTrials.gov Identifier:

NCT03034967

Other Study ID Numbers:

205724
2016-003675-21

First Posted:

Jan 27, 2017

Last Update Posted:

Oct 28, 2020

Last Verified:

Oct 1, 2020