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The aim of this First Time in Patient study is to obtain initial information on the safety, tolerability, pharmacokinetics, pharmacodynamics and clinical efficacy of repeat daily administration of danirixin in subjects with symptomatic chronic obstructive pulmonary disease (COPD) having mild to moderate airflow limitation and are at high risk for future COPD exacerbations.
The study will be conducted in two parts. Part A will be a two week open label, single arm study in patients with COPD to obtain pharmacokinetic data and safety information of repeat dosing of danirixin in the population of interest. Approximately 10 subjects will be enrolled in Part A of the study. Progression to and dose selection for Part B will occur following review of the data collected in Part A. Part B will be a 52-week, randomized, double-blind (sponsor unblind), placebo-controlled on top of standard of care, parallel group study. Part B will evaluate several clinical efficacy assessments related to exacerbations and respiratory symptoms. Approximately 100 subjects will be enrolled with a target of 80 subjects completing 52 weeks of danirixin administration.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Part A | Experimental | Subjects will receive 50 mg danirixin twice daily (BID) orally for 14 days. If the exposure to danirixin is lower than expected, after 14 days of dosing, then the dose may be increased to 75 mg BID for Part B. |
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| Part B | Experimental | Subjects will be randomized to receive either danirixin BID or placebo BID treatment along with standard care of treatment for 52 weeks. Subjects completing Part A and meeting the eligibility criteria for Part B could also be randomized in Part B. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Danirixin | Drug | Danirixin is available as 50 or 75 mg white, film coated immediate release tablet. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants With Any Adverse Event (AE) and, Serious Adverse Event (SAE) in Part A | An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention, events associated with liver injury and impaired liver function were categorized as SAE. Participants with any AE or SAE were summarized. Participants with AE or SAE occurrences >= 5 percent were summarized. All Subjects Population comprised of all participants who were screened and for whom a record existed on the study database. | Up to Day 28 in Part A |
| Number of Participants With Any AE and SAE in Part B | An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention, events associated with liver injury and impaired liver function were categorized as SAE. Participants with AE or SAE occurrences >= 5 percent were summarized. | Up to Day 392 in Part B |
| Number of Participants With Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Pulse Rate, Respiratory Rate and Body Temperature Abnormalities of Potential Clinical Importance in Part A | Vital signs including SBP, DBP, pulse rate, respiratory rate and body temperature were taken on Day 1 pre-dose and on Day 14 and at Follow-up (Day 21 to 28) in Part A. Measurements were obtained in a semi-supine/ supine position after 5 minutes rest. The mean of replicate assessments at any given time point was used as the value for that time point. SBP <90 or >160 millimeter of mercury (mmHg); DBP <40 or >110 mmHg, pulse rate <35 or >120 beats per minute (bpm) and respiratory rate <8 or >30 breaths per minute were considered as values of potential clinical importance and were presented as 'High' or 'Low' values. Intent-to-Treat (ITT) Population comprised of all randomized par. who received at least one dose of study medication. |
| Measure | Description | Time Frame |
|---|---|---|
| Cmax of Danirixin in Part B | Cmax of danirixin was derived from the PK samples collected at pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 364; and at pre-dose and 2 hours on Day 28, 56 and 168 in Part B. PK analysis of danirixin was conducted by non-compartmental methods. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| GSK Clinical Trials | GlaxoSmithKline | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| GSK Investigational Site | Birmingham | Alabama | 35294 | United States | ||
| GSK Investigational Site |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30139779 | Derived | Lazaar AL, Miller BE, Tabberer M, Yonchuk J, Leidy N, Ambery C, Bloomer J, Watz H, Tal-Singer R. Effect of the CXCR2 antagonist danirixin on symptoms and health status in COPD. Eur Respir J. 2018 Oct 4;52(4):1801020. doi: 10.1183/13993003.01020-2018. Print 2018 Oct. No abstract available. |
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A total of 19 par. in Part A were screened (10 failed) and 9 were randomized in a 2-week treatment period (TP) followed by a follow-up visit (FU) at 7- 14 days after last dose. A total of 127 par. in Part B were screened (34 failed) and 93 were randomized in a 52-week TP followed by a FU at 14- 28 days after last dose of the study.
This was a 2 part study. In Part A, an open label, single arm, participants (par.) received danrixin 50 milligrams (mg) twice daily (BID) for 2 weeks. In Part B, a randomized (1:1), double-blind (sponsor unblinded) placebo controlled on top of standard of care study, par. received DNX 75 mg BID in one arm and placebo in the other arm for 52 weeks.
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| ID | Title | Description |
|---|---|---|
| FG000 | Part A: 4-week Open-label Period: DNX 50 mg | Participants received one immediate release tablet of danirixin (DNX) 50 mg BID with food and water for 2 weeks. Participants were permitted to continue taking inhaled maintenance medications. Rescue medications for acute symptoms were also permitted (e.g. short acting bronchodilators). |
| FG001 |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Part A: 4-week Open-label Period |
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| Placebo | Drug | Subjects will receive danirixin matching placebo |
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| Up to Day 28 in Part A |
| Number of Participants With Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Pulse Rate and Respiratory Rate Abnormalities of Potential Clinical Importance in Part B | Vital signs including SBP, DBP, pulse rate and respiratory rate were taken on Day 1 pre-dose and on Day 28, 56, 112, 168, 280, 364 and at Follow-up (Day 378 to 392) in Part B. Measurements were obtained in a semi-supine/ supine position after 5 minutes rest. The mean of replicate assessments at any given time point was used as the value for that time point. SBP <90 or >160 mmHg, DBP <40 or >110 mmHg, pulse rate <35 or >120 bpm and respiratory rate <8 or >30 breaths per minute were considered as values of potential clinical importance and were presented as 'High' or 'Low' values. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | Up to Day 392 in Part B |
| Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) in Part A | 12-lead ECG was taken on Day 1 pre-dose and on Follow-up visit (Day 21 to 28) in Part A using an ECG machine. Triplicate reading were taken on Day 1 pre-dose. Participants with abnormal-clinically not significant (NCS) and abnormal-clinically significant (CS) findings were sumarized. | Up to Day 28 in Part A |
| Number of Participants With Abnormal 12-lead ECG in Part B | 12-lead ECG was taken on Day 1 pre-dose and on Day 28, 168 and at Follow-up (Day 378 to 392) in Part B using an ECG machine. Participants with abnormal-NCS and abnormal-CS findings were sumarized. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | Up to Day 392 in Part B |
| Number of Participants With Hematology Values of Potential Clinical Importance in Part A | Blood samples were collected at Screening and Day 14 in Part A to evaluate hematology parameters which included hemoglobin, hematocrit, basophils, eosinophils, lymphocytes, monocytes, neutrophils, mean corpuscular hemoglobin concentration (MCHC), mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), red blood cell (RBC) count, white blood cell (WBC) count, platelet count and reticulocyte count. Hematology values of potential clinical importance were presented as 'High' or 'Low' values based on the reference laboratory standards. | Up to Day 28 in Part A |
| Number of Participants With Hematology Values of Potential Clinical Importance in Part B | Blood samples were collected at Screening and on Day 28, 168, and 364 in Part B to evaluate hematology parameters which included hemoglobin, hematocrit, basophils, eosinophils, lymphocytes, monocytes, neutrophils, MCHC, MCH, MCV, RBC count, WBC count, platelet count and reticulocyte count. Hematology values of potential clinical importance were presented as 'High' or 'Low' values based on the reference laboratory standards. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | Up to Day 392 in Part B |
| Number of Participants With Clinical Chemistry Values of Potential Clinical Importance in Part A | Blood samples were collected at Screening and Day 14 in Part A to evaluate clinical chemistry parameters which included alanine aminotransferase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), total bilirubin, calcium, bicarbonate, chloride, creatinine, direct bilirubin, gamma glutamyl transferase (GGT), glucose, potassium, total protein, sodium, blood urea nitrogen (BUN) and uric acid. Additional liver monitoring chemistry (ALT, AST, ALP and total and direct bilirubin) was done on Day 1 pre-dose. Clinical chemistry values of potential clinical importance were presented as 'High' or 'Low' values based on the reference laboratory standards. | Up to Day 28 in Part A |
| Number of Participants With Clinical Chemistry Values of Potential Clinical Importance in Part B | Blood samples were collected at Screening and on Day 28, 168 and 364 in Part B to evaluate clinical chemistry parameters which included ALT, albumin, ALP, AST, total bilirubin, calcium, bicarbonate, chloride, creatinine, direct bilirubin, GGT, glucose, potassium, total protein, sodium, BUN and uric acid. Clinical chemistry values of potential clinical importance were presented as 'High' or 'Low' values based on the reference laboratory standards. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | Up to Day 392 in Part B |
| Number of Participants With Urinalysis Dipstick Results in Part A | Test strip urinalysis was done for glucose, ketones, occult blood and protein at Screening and Day 14 in Part A. Results were presented as negative, trace, 1+, 2+ and 3+ for glucose, ketones, occult blood and protein. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). | Up to Day 28 in Part A |
| Number of Participants With Urinalysis Dipstick Results in Part B | Test strip urinalysis was done for glucose, ketones, occult blood and protein at Screening and on Day 28, 168, 224 and 364 in Part B. Results were presented as negative, trace, 1+, 2+ and 3+ for glucose, ketones, occult blood and protein. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | Up to Day 392 in Part B |
| Change From Baseline in Urine Power of Hydrogen (pH) at Day 14 in Part A | Urinalysis including urine pH was done at Screening and Day 14 in Part A. Baseline was considered as the measurement obtained at Screening (Day -1). The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. | Up to Day 28 in Part A |
| Change From Baseline in Urine pH in Part B | Urinalysis including urine pH was done at Screening and on Day 28, 168 and 364 in Part B. Baseline was considered as the measurement obtained at Screening (Day -1). The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | Up to Day 392 in Part B |
| Change From Baseline in Urine Specific Gravity of Urine in Part A | Urinalysis including urine specific gravity was done at Screening and Day 14 in Part A. Baseline was considered as the measurement obtained at Screening (Day -1). The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. | Up to Day 28 in Part A |
| Change From Baseline in Urine Specific Gravity of Urine in Part B | Urinalysis including urine specific gravity was done at Screening and on Day 28, 168 and 364 in Part B. Baseline was considered as the measurement obtained at Screening (Day -1). The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. | Up to Day 392 in Part B |
| Change From Baseline in Forced Expiratory Volume in One Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points in Part A | FEV1 measures how much air a person can exhale during a forced breath in 1 second. FVC is the total amount of air exhaled during the FEV test. FEV1 and FVC were performed at Screening and on Day 1, 14 and at Follow-up visit (Day 21 to 28). FEV1 and FVC assessments at each time point (post-bronchodilator) were taken in triplicate. The maximum of the triplicate assessments were used. Baseline was considered as the measurement obtained at Day 1 pre-dose. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. | Up to Day 28 in Part A |
| Change From Baseline in FEV1 and FVC at the Indicated Time Points in Part B | FEV1 and FVC were performed at Screening and on Day 1, 28, 56, 112, 168, 280, 364 and at Follow-up (Day 378 to 392) in Part B. FEV1 and FVC assessments at each time point (post-bronchodilator) were taken in triplicate. The maximum of the triplicate assessments were used. Baseline was considered as the measurement obtained at Day 1 pre-dose. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Statistical analysis was performed using a repeated measures mixed effects model in a Bayesian framework. The estimate of the treatment difference and corresponding 95 percent credible interval was constructed for the difference between danirixin and placebo for each visit. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). | Up to Day 392 in Part B |
| Maximum Observed Plasma Concentration (Cmax) of Danirixin in Part A | Cmax of danirixin was derived from the Pharmacokinetics (PK) samples collected at pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 14 in Part A. PK analysis of danirixin was conducted by non-compartmental methods. PK Concenteration Population comprised of par. in the ITT Population and who had provided at least one on-treatment blood sample for determination of danirixin concentration. | Pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 14 in Part A |
| Time of Occurrence of Cmax (Tmax) of Danirixin in Part A | Tmax of danirixin was derived from the PK samples collected at pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 14 in Part A. PK analysis of danirixin was conducted by non-compartmental methods. | Pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 14 in Part A |
| Area Under the Blood Concentration-time Curve (AUC) Over Dosing Interval (AUC[0-12]) of Danirixin in Part A | AUC (0-12) of danirixin was derived from the PK samples collected at pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 14 in Part A. PK analysis of danirixin was conducted by non-compartmental methods. A Bayesian random effects model was performed adjusting for the trial as a random effect. A non-informative normal prior distribution was used. Point estimates and corresponding 90 percent credible intervals were constructed. | Pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 14 in Part A |
| Number of Health Care Resource Utilization (HCRU) Defined COPD Exacerbations Per Year in Part B | HCRU COPD exacerbations are defined as moderate or severe exacerbations based on requirement of new prescription antibiotics or oral corticosteroids, hospitalization or emergency room visits for management of COPD exacerbation. For par. with less than 364 days on-treatment, the annual exacerbation rate was imputed as the number of recorded on-treatment exacerbations, divided by the number of 4-week treatment period intervals for which the par. was in the study, multiplied by 13. For par. with 364 or more days on-treatment, the annual exacerbation rate was calculated as the number of recorded exacerbations between study days 1 and 364. Statistical analysis was done using a Bayesian Cox model, assuming a negative binomial distribution for the underlying exacerbation rate. The exacerbation rates along with the ratio (danirixin/placebo), were estimated and corresponding 95 percent credible intervals were produced using non-informative priors. 1 par. was excluded from the analysis. | Up to Day 392 in Part B |
| Monthly Weighted Means of Exacerbations of Chronic Pulmonary Disease Tool-respiratory Symptoms (EXACT-RS) Total Score in Part B | EXACT-RS is a tool which consists of 11 items from the 14 item EXACT- patient reported outcomes (EXACT-PRO) instrument, intended to capture information related to the respiratory symptoms of COPD, i.e. breathlessness, cough, sputum production, chest congestion and chest tightness. The EXACT-RS has a scoring range of 0-40, higher scores indicate more severe symptoms. A par. had at least 10 days of diary data in any month to contribute a non-missing weighted mean AUC of daily values; otherwise the weighted mean for that month were considered missing. A mixed effects model in a Bayesian framework with repeated measures were performed on the EXACT-RS monthly weighted mean AUC data. The posterior mean and corresponding 95 percent credible interval were calculated. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | Up to Day 392 in Part B |
| Pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 364; and at pre-dose and 2 hours on Day 28, 56 and 168 in Part B |
| Tmax of Danirixin in Part B | Tmax of danirixin was derived from the PK samples collected at pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 364; and at pre-dose and 2 hours on Day 28, 56 and 168 in Part B. PK analysis of danirixin was conducted by non-compartmental methods. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). | Pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 364; and at pre-dose and 2 hours on Day 28, 56 and 168 in Part B |
| AUC(0-12) of Danirixin in Part B | AUC (0-12) of danirixin was derived from the PK samples collected at pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 364; and at pre-dose and 2 hours on Day 28, 56 and 168 in Part B. PK analysis of danirixin was conducted by non-compartmental methods. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). | Pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 364; and at pre-dose and 2 hours on Day 28, 56 and 168 in Part B |
| Number of EXACT-PRO Exacerbations Per Year in Part B | EXACT-PRO is a 14 item patient reported outcome instrument designed to capture information on the occurrence, frequency, severity, and duration of COPD exacerbations. The total score for EXACT-PRO ranges from 0-100, higher scores indicate more severe symptoms. For par. with less than 364 days on-treatment, the annual exacerbation rate was imputed as the number of recorded on-treatment exacerbations, divided by the number of 4-week treatment period intervals for which the par. was in the study, multiplied by 13. For par. with 364 or more days on-treatment, the annual exacerbation rate was calculated as the number of recorded exacerbations between study days 1 and 364. Statistical analysis was done using a Bayesian Cox model, assuming a negative binomial distribution for the underlying exacerbation rate. The exacerbation rates and the ratio (danirixin/placebo), were estimated and 95 percent credible intervals were produced using non-informative priors. 1 par. was excluded from analysis. | Up to Day 392 in Part B |
| Monthly Weighted Means of Exacerbations of EXACT-PRO Total Score in Part B | EXACT-PRO is a 14 item patient reported outcome instrument designed to capture information on the occurrence, frequency, severity, and duration of COPD exacerbations. The total score for EXACT-PRO ranges from 0-100, higher scores indicate more severe symptoms. A par. had at least 10 days of diary data in any month to contribute a non-missing weighted mean AUC of daily values; otherwise the weighted mean for that month were considered missing. A mixed effects model in a Bayesian framework with repeated measures were performed on the EXACT-PRO monthly weighted mean AUC data. The posterior mean and corresponding 95 percent credible interval were calculated. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | Up to Day 392 in Part B |
| Time to First HCRU COPD Exacerbation in Part B | HCRU COPD exacerbations are defined as moderate or severe exacerbations based on requirement of new prescription antibiotics or oral corticosteroids, hospitalization or emergency room visits for management of COPD exacerbation. The time to the first on-treatment HRCU exacerbation were summarized by treatment group. It was analyzed using a Bayesian Cox proportional hazards model. The hazard ratio for the danirixin vs. placebo comparison, along with 95 percent credible interval, was derived, with terms for treatment group, smoking status and country. Posterior probabilities of the ratio of the percentage of par. with an HCRU exacerbation, adjusted for time to first exacerbation, in the danirixin group relative to the placebo group were calculated. 1 par. was excluded from analysis. | Up to Day 392 in Part B |
| Time to First EXACT-PRO Event in Part B | The hazard ratio for the DNX versus placebo comparison, along with 95% credible interval and posterior probability was derived and a Bayesian Cox proportional hazards model was used for statistical analysis. The analysis was performed on ITT Population. One participant was excluded from analysis. | Up to Day 392 in Part B |
| Assessment of Duration of EXACT-PRO Events in Part B | Duration is the length of time in days from onset to recovery. It was calculated as the difference in days between day of onset and day of recovery. Onset of event was identified as either an increase in EXACT-PRO score of >=12 points above the par. current mean Baseline for 2 consecutive days, with Day 1 of the 2 days serving as Day 1 onset of the event, or an increase of >=9 points above the par. current mean Baseline for 3 consecutive days, with Day 1 of the 3 days serving as Day 1 onset of the event. Duration was 3-day rolling average was used, which was initiated on Day 1 of onset and ended on Day 1 of Recovery. Recovery was defined as the first day in which par. experienced a persistent, sustained improvement in their condition i.e. decrease in the rolling average EXACT-PRO total score >=9 point from the maximum observed value (highest rolling average EXACT-PRO total score observed the first 14 days of the event) during the first 14 days of an event that is sustained for 7 days. | Up to Day 392 in Part B |
| Assessment of Severity of EXACT-PRO Events in Part B | EXACT-PRO tool was used to measure severity of COPD exacerbations in participants. Severity was indicated by the maximum EXACT-PRO total score during the course of event (from day of onset to day of recovery). | Up to Day 392 in Part B |
| Monthly Weighted Means of EXACT-RS Domain Scores in Part B | EXACT-RS is a tool which consists of 11 items from the 14 item EXACT-PRO instrument, intended to capture information related to the respiratory symptoms of COPD. EXACT-RS domains included breathlessness, cough and chest symptoms. The EXACT-RS has a scoring range of 0-40, higher scores indicate more severe symptoms. A par. had at least 10 days of diary data in any month to contribute a non-missing weighted mean AUC of daily values; otherwise the weighted mean for that month were considered missing. A mixed effects model in a Bayesian framework with repeated measures were performed. The posterior mean and corresponding 95 percent credible interval were calculated. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | Up to Day 392 in Part B |
| Change From Baseline for COPD Assessment Test (CAT) at the Indicated Time Points in Part B | The CAT is a validated, 8 item questionnaire which has been developed designed to measure overall COPD-related health status for the initial assessment and longitudinal follow up of par. with COPD. Participants completed each question by rating their experience on a 6 point scale ranging from 0 (no impairment) to 5 (maximum impairment) with a total scoring range of 0 - 40. CAT was assessed at Baseline (Day 1), Day 28, Day 112, Day 168, Day 280 and Day 364 where Baseline was considered as score on Day 1. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | Up to Day 392 in Part B |
| Number of Participants With Physician's Global Assessment (PGA) Readings in Part B | The PGA is a single item clinician reported outcome measure assessing the overall severity of COPD. Physicians rated disease severity on a four point scale ranging from 1-4 (1=mild, 2=moderate, 3=severe, 4=very severe) at Week 0, 4, 8, 16, 24, 40 and 52. Baseline was considered as score on Day 1. A categorical summary of PGA is presented by treatment and visit.Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | Up to Day 392 in Part B |
| Number of Participants With Patient Global Rating of Severity (PGRS) Score in Part B | PGRS is a single global question and was asked to participants to rate their COPD severity on a four point scale ranging from 1-4 (1=mild, 2=moderate, 3=severe, 4=very severe). Participants completed PGRS at Week 0, 4, 8, 16, 24, 40 and 52. Baseline was considered as score on Day 1. A categorical summary of PGRS is presented by treatment and visit.Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | Up to Day 392 in Part B |
| Number of Participants With Patient Global Impression of Change (PGIC)Score in Part B | Participants completed a PGIC questions at Week 4, 8, 16, 24, 40 and 52. Response options were on a 7 point Likert scale ranging from much better to much worse. PGIC was re-coded from a categorical to numerical value prior to analysis as: much worse = -3, worse = -2, slightly worse = -1, no change = 0, slightly better = 1, better = 2, much better = 3.A categorical summary of PGIC is presented by treatment and visit.Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | Up to Day 392 in Part B |
| Denver |
| Colorado |
| 80206 |
| United States |
| GSK Investigational Site | Iowa City | Iowa | 52242 | United States |
| GSK Investigational Site | Oaks | Pennsylvania | 19456 | United States |
| GSK Investigational Site | Philadelphia | Pennsylvania | 19140 | United States |
| GSK Investigational Site | Spartanburg | South Carolina | 29303 | United States |
| GSK Investigational Site | Frankfurt am Main | Hesse | 60596 | Germany |
| GSK Investigational Site | Neu-Isenburg | Hesse | 63263 | Germany |
| GSK Investigational Site | Düren | North Rhine-Westphalia | 52349 | Germany |
| GSK Investigational Site | Essen | North Rhine-Westphalia | 45359 | Germany |
| GSK Investigational Site | Leipzig | Saxony | 04207 | Germany |
| GSK Investigational Site | Leipzig | Saxony | 04275 | Germany |
| GSK Investigational Site | Magdeburg | Saxony-Anhalt | 39112 | Germany |
| GSK Investigational Site | Großhansdorf | Schleswig-Holstein | 22927 | Germany |
| GSK Investigational Site | Berlin | 10787 | Germany |
| GSK Investigational Site | Berlin | 10789 | Germany |
| Part B: 52-week Double-blind Period: Placebo |
Participants received one tablet of placebo twice daily with food and water for 52 weeks. It was administered on top of the participant's current standard of care. Participants were permitted to continue taking inhaled maintenance medications. Rescue medications for acute symptoms were also permitted (e.g. short acting bronchodilators). |
| FG002 | Part B: 52-week Double-blind Period: DNX 75 mg | Participants received one immediate release tablet of danirixin (DNX) 75 mg BID with food and water for 52 weeks. It was administered on top of the participant's current standard of care. Participants were permitted to continue taking inhaled maintenance medications. Rescue medications for acute symptoms were also permitted (e.g. short acting bronchodilators). |
| COMPLETED |
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| NOT COMPLETED |
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| Part B: 52-week Double-blind Period |
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Data for Part B is presented.
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| ID | Title | Description |
|---|---|---|
| BG000 | Placebo | Participants received one tablet of placebo twice daily with food and water for 52 weeks. It was administered on top of the participant's current standard of care. Participants were permitted to continue taking inhaled maintenance medications. Rescue medications for acute symptoms were also permitted (e.g. short acting bronchodilators). |
| BG001 | DNX 75 mg | Participants received one immediate release tablet of danirixin (DNX) 75 mg BID with food and water for 52 weeks. It was administered on top of the participant's current standard of care. Participants were permitted to continue taking inhaled maintenance medications. Rescue medications for acute symptoms were also permitted (e.g. short acting bronchodilators). |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
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| Age, Continuous | Mean | Standard Deviation | Years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Number | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||
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| Primary | Number of Participants With Any Adverse Event (AE) and, Serious Adverse Event (SAE) in Part A | An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention, events associated with liver injury and impaired liver function were categorized as SAE. Participants with any AE or SAE were summarized. Participants with AE or SAE occurrences >= 5 percent were summarized. All Subjects Population comprised of all participants who were screened and for whom a record existed on the study database. | All Subjects Population | Posted | Number | Participants | Up to Day 28 in Part A |
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| Primary | Number of Participants With Any AE and SAE in Part B | An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Any untoward event resulting in death, life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, congenital anomaly/birth defect, any other situation according to medical or scientific judgment that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention, events associated with liver injury and impaired liver function were categorized as SAE. Participants with AE or SAE occurrences >= 5 percent were summarized. | All Subjects Population | Posted | Number | Participants | Up to Day 392 in Part B |
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| Primary | Number of Participants With Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Pulse Rate, Respiratory Rate and Body Temperature Abnormalities of Potential Clinical Importance in Part A | Vital signs including SBP, DBP, pulse rate, respiratory rate and body temperature were taken on Day 1 pre-dose and on Day 14 and at Follow-up (Day 21 to 28) in Part A. Measurements were obtained in a semi-supine/ supine position after 5 minutes rest. The mean of replicate assessments at any given time point was used as the value for that time point. SBP <90 or >160 millimeter of mercury (mmHg); DBP <40 or >110 mmHg, pulse rate <35 or >120 beats per minute (bpm) and respiratory rate <8 or >30 breaths per minute were considered as values of potential clinical importance and were presented as 'High' or 'Low' values. Intent-to-Treat (ITT) Population comprised of all randomized par. who received at least one dose of study medication. | ITT Population | Posted | Number | Participants | Up to Day 28 in Part A |
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| Primary | Number of Participants With Systolic Blood Pressure (SBP), Diastolic Blood Pressure (DBP), Pulse Rate and Respiratory Rate Abnormalities of Potential Clinical Importance in Part B | Vital signs including SBP, DBP, pulse rate and respiratory rate were taken on Day 1 pre-dose and on Day 28, 56, 112, 168, 280, 364 and at Follow-up (Day 378 to 392) in Part B. Measurements were obtained in a semi-supine/ supine position after 5 minutes rest. The mean of replicate assessments at any given time point was used as the value for that time point. SBP <90 or >160 mmHg, DBP <40 or >110 mmHg, pulse rate <35 or >120 bpm and respiratory rate <8 or >30 breaths per minute were considered as values of potential clinical importance and were presented as 'High' or 'Low' values. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | ITT Population | Posted | Number | Participants | Up to Day 392 in Part B |
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| Primary | Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) in Part A | 12-lead ECG was taken on Day 1 pre-dose and on Follow-up visit (Day 21 to 28) in Part A using an ECG machine. Triplicate reading were taken on Day 1 pre-dose. Participants with abnormal-clinically not significant (NCS) and abnormal-clinically significant (CS) findings were sumarized. | ITT Population | Posted | Number | Participants | Up to Day 28 in Part A |
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| Primary | Number of Participants With Abnormal 12-lead ECG in Part B | 12-lead ECG was taken on Day 1 pre-dose and on Day 28, 168 and at Follow-up (Day 378 to 392) in Part B using an ECG machine. Participants with abnormal-NCS and abnormal-CS findings were sumarized. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | ITT Population | Posted | Number | Participants | Up to Day 392 in Part B |
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| Primary | Number of Participants With Hematology Values of Potential Clinical Importance in Part A | Blood samples were collected at Screening and Day 14 in Part A to evaluate hematology parameters which included hemoglobin, hematocrit, basophils, eosinophils, lymphocytes, monocytes, neutrophils, mean corpuscular hemoglobin concentration (MCHC), mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), red blood cell (RBC) count, white blood cell (WBC) count, platelet count and reticulocyte count. Hematology values of potential clinical importance were presented as 'High' or 'Low' values based on the reference laboratory standards. | ITT Population | Posted | Number | Participants | Up to Day 28 in Part A |
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| Primary | Number of Participants With Hematology Values of Potential Clinical Importance in Part B | Blood samples were collected at Screening and on Day 28, 168, and 364 in Part B to evaluate hematology parameters which included hemoglobin, hematocrit, basophils, eosinophils, lymphocytes, monocytes, neutrophils, MCHC, MCH, MCV, RBC count, WBC count, platelet count and reticulocyte count. Hematology values of potential clinical importance were presented as 'High' or 'Low' values based on the reference laboratory standards. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | ITT Population | Posted | Number | Participants | Up to Day 392 in Part B |
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| Primary | Number of Participants With Clinical Chemistry Values of Potential Clinical Importance in Part A | Blood samples were collected at Screening and Day 14 in Part A to evaluate clinical chemistry parameters which included alanine aminotransferase (ALT), albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), total bilirubin, calcium, bicarbonate, chloride, creatinine, direct bilirubin, gamma glutamyl transferase (GGT), glucose, potassium, total protein, sodium, blood urea nitrogen (BUN) and uric acid. Additional liver monitoring chemistry (ALT, AST, ALP and total and direct bilirubin) was done on Day 1 pre-dose. Clinical chemistry values of potential clinical importance were presented as 'High' or 'Low' values based on the reference laboratory standards. | ITT Population | Posted | Number | Participants | Up to Day 28 in Part A |
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| Primary | Number of Participants With Clinical Chemistry Values of Potential Clinical Importance in Part B | Blood samples were collected at Screening and on Day 28, 168 and 364 in Part B to evaluate clinical chemistry parameters which included ALT, albumin, ALP, AST, total bilirubin, calcium, bicarbonate, chloride, creatinine, direct bilirubin, GGT, glucose, potassium, total protein, sodium, BUN and uric acid. Clinical chemistry values of potential clinical importance were presented as 'High' or 'Low' values based on the reference laboratory standards. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | ITT Population | Posted | Number | Participants | Up to Day 392 in Part B |
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| Primary | Number of Participants With Urinalysis Dipstick Results in Part A | Test strip urinalysis was done for glucose, ketones, occult blood and protein at Screening and Day 14 in Part A. Results were presented as negative, trace, 1+, 2+ and 3+ for glucose, ketones, occult blood and protein. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). | ITT Population | Posted | Number | Participants | Up to Day 28 in Part A |
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| Primary | Number of Participants With Urinalysis Dipstick Results in Part B | Test strip urinalysis was done for glucose, ketones, occult blood and protein at Screening and on Day 28, 168, 224 and 364 in Part B. Results were presented as negative, trace, 1+, 2+ and 3+ for glucose, ketones, occult blood and protein. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | ITT Population | Posted | Number | Participants | Up to Day 392 in Part B |
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| Primary | Change From Baseline in Urine Power of Hydrogen (pH) at Day 14 in Part A | Urinalysis including urine pH was done at Screening and Day 14 in Part A. Baseline was considered as the measurement obtained at Screening (Day -1). The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. | ITT Population | Posted | Mean | Standard Deviation | pH | Up to Day 28 in Part A |
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| Primary | Change From Baseline in Urine pH in Part B | Urinalysis including urine pH was done at Screening and on Day 28, 168 and 364 in Part B. Baseline was considered as the measurement obtained at Screening (Day -1). The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | ITT Population | Posted | Mean | Standard Deviation | pH | Up to Day 392 in Part B |
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| Primary | Change From Baseline in Urine Specific Gravity of Urine in Part A | Urinalysis including urine specific gravity was done at Screening and Day 14 in Part A. Baseline was considered as the measurement obtained at Screening (Day -1). The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. | ITT Population | Posted | Mean | Standard Deviation | urine specific gravity | Up to Day 28 in Part A |
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| Primary | Change From Baseline in Urine Specific Gravity of Urine in Part B | Urinalysis including urine specific gravity was done at Screening and on Day 28, 168 and 364 in Part B. Baseline was considered as the measurement obtained at Screening (Day -1). The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. | ITT Population | Posted | Mean | Standard Deviation | urine specific gravity | Up to Day 392 in Part B |
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| Primary | Change From Baseline in Forced Expiratory Volume in One Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points in Part A | FEV1 measures how much air a person can exhale during a forced breath in 1 second. FVC is the total amount of air exhaled during the FEV test. FEV1 and FVC were performed at Screening and on Day 1, 14 and at Follow-up visit (Day 21 to 28). FEV1 and FVC assessments at each time point (post-bronchodilator) were taken in triplicate. The maximum of the triplicate assessments were used. Baseline was considered as the measurement obtained at Day 1 pre-dose. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. | ITT Population | Posted | Mean | Standard Deviation | Liter | Up to Day 28 in Part A |
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| Primary | Change From Baseline in FEV1 and FVC at the Indicated Time Points in Part B | FEV1 and FVC were performed at Screening and on Day 1, 28, 56, 112, 168, 280, 364 and at Follow-up (Day 378 to 392) in Part B. FEV1 and FVC assessments at each time point (post-bronchodilator) were taken in triplicate. The maximum of the triplicate assessments were used. Baseline was considered as the measurement obtained at Day 1 pre-dose. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Statistical analysis was performed using a repeated measures mixed effects model in a Bayesian framework. The estimate of the treatment difference and corresponding 95 percent credible interval was constructed for the difference between danirixin and placebo for each visit. Only those participants available at the specified time points were analyzed (represented by n=X, X in the category titles). | ITT Population | Posted | Mean | Standard Deviation | Liter | Up to Day 392 in Part B |
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| Primary | Maximum Observed Plasma Concentration (Cmax) of Danirixin in Part A | Cmax of danirixin was derived from the Pharmacokinetics (PK) samples collected at pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 14 in Part A. PK analysis of danirixin was conducted by non-compartmental methods. PK Concenteration Population comprised of par. in the ITT Population and who had provided at least one on-treatment blood sample for determination of danirixin concentration. | PK Population | Posted | Geometric Mean | 95% Confidence Interval | Nanogram per milliliter (ng/mL) | Pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 14 in Part A |
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| Primary | Time of Occurrence of Cmax (Tmax) of Danirixin in Part A | Tmax of danirixin was derived from the PK samples collected at pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 14 in Part A. PK analysis of danirixin was conducted by non-compartmental methods. | PK Population | Posted | Median | Full Range | Hour | Pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 14 in Part A |
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| Primary | Area Under the Blood Concentration-time Curve (AUC) Over Dosing Interval (AUC[0-12]) of Danirixin in Part A | AUC (0-12) of danirixin was derived from the PK samples collected at pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 14 in Part A. PK analysis of danirixin was conducted by non-compartmental methods. A Bayesian random effects model was performed adjusting for the trial as a random effect. A non-informative normal prior distribution was used. Point estimates and corresponding 90 percent credible intervals were constructed. | PK Population | Posted | Geometric Mean | 95% Confidence Interval | Hour*ng/mL | Pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 14 in Part A |
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| Primary | Number of Health Care Resource Utilization (HCRU) Defined COPD Exacerbations Per Year in Part B | HCRU COPD exacerbations are defined as moderate or severe exacerbations based on requirement of new prescription antibiotics or oral corticosteroids, hospitalization or emergency room visits for management of COPD exacerbation. For par. with less than 364 days on-treatment, the annual exacerbation rate was imputed as the number of recorded on-treatment exacerbations, divided by the number of 4-week treatment period intervals for which the par. was in the study, multiplied by 13. For par. with 364 or more days on-treatment, the annual exacerbation rate was calculated as the number of recorded exacerbations between study days 1 and 364. Statistical analysis was done using a Bayesian Cox model, assuming a negative binomial distribution for the underlying exacerbation rate. The exacerbation rates along with the ratio (danirixin/placebo), were estimated and corresponding 95 percent credible intervals were produced using non-informative priors. 1 par. was excluded from the analysis. | ITT Population | Posted | Mean | Standard Deviation | Exacerbations per year | Up to Day 392 in Part B |
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| Primary | Monthly Weighted Means of Exacerbations of Chronic Pulmonary Disease Tool-respiratory Symptoms (EXACT-RS) Total Score in Part B | EXACT-RS is a tool which consists of 11 items from the 14 item EXACT- patient reported outcomes (EXACT-PRO) instrument, intended to capture information related to the respiratory symptoms of COPD, i.e. breathlessness, cough, sputum production, chest congestion and chest tightness. The EXACT-RS has a scoring range of 0-40, higher scores indicate more severe symptoms. A par. had at least 10 days of diary data in any month to contribute a non-missing weighted mean AUC of daily values; otherwise the weighted mean for that month were considered missing. A mixed effects model in a Bayesian framework with repeated measures were performed on the EXACT-RS monthly weighted mean AUC data. The posterior mean and corresponding 95 percent credible interval were calculated. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | ITT Population | Posted | Mean | Standard Deviation | Score on a scale | Up to Day 392 in Part B |
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| Secondary | Cmax of Danirixin in Part B | Cmax of danirixin was derived from the PK samples collected at pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 364; and at pre-dose and 2 hours on Day 28, 56 and 168 in Part B. PK analysis of danirixin was conducted by non-compartmental methods. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). | PK Population | Posted | Geometric Mean | 95% Confidence Interval | ng/mL | Pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 364; and at pre-dose and 2 hours on Day 28, 56 and 168 in Part B |
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| Secondary | Tmax of Danirixin in Part B | Tmax of danirixin was derived from the PK samples collected at pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 364; and at pre-dose and 2 hours on Day 28, 56 and 168 in Part B. PK analysis of danirixin was conducted by non-compartmental methods. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). | PK Population | Posted | Median | Full Range | Hour | Pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 364; and at pre-dose and 2 hours on Day 28, 56 and 168 in Part B |
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| Secondary | AUC(0-12) of Danirixin in Part B | AUC (0-12) of danirixin was derived from the PK samples collected at pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 364; and at pre-dose and 2 hours on Day 28, 56 and 168 in Part B. PK analysis of danirixin was conducted by non-compartmental methods. Only those participants with data available at the specified time points were analyzed (represented by n=X in the category titles). | PK Population | Posted | Geometric Mean | 95% Confidence Interval | Hour*ng/mL | Pre-dose and at 0.5, 1, 2, 4, 6, 8, 10 and 12 hour post-dose on Day 1 and Day 364; and at pre-dose and 2 hours on Day 28, 56 and 168 in Part B |
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| Secondary | Number of EXACT-PRO Exacerbations Per Year in Part B | EXACT-PRO is a 14 item patient reported outcome instrument designed to capture information on the occurrence, frequency, severity, and duration of COPD exacerbations. The total score for EXACT-PRO ranges from 0-100, higher scores indicate more severe symptoms. For par. with less than 364 days on-treatment, the annual exacerbation rate was imputed as the number of recorded on-treatment exacerbations, divided by the number of 4-week treatment period intervals for which the par. was in the study, multiplied by 13. For par. with 364 or more days on-treatment, the annual exacerbation rate was calculated as the number of recorded exacerbations between study days 1 and 364. Statistical analysis was done using a Bayesian Cox model, assuming a negative binomial distribution for the underlying exacerbation rate. The exacerbation rates and the ratio (danirixin/placebo), were estimated and 95 percent credible intervals were produced using non-informative priors. 1 par. was excluded from analysis. | ITT Population | Posted | Mean | Standard Deviation | Exacerbations per year | Up to Day 392 in Part B |
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| Secondary | Monthly Weighted Means of Exacerbations of EXACT-PRO Total Score in Part B | EXACT-PRO is a 14 item patient reported outcome instrument designed to capture information on the occurrence, frequency, severity, and duration of COPD exacerbations. The total score for EXACT-PRO ranges from 0-100, higher scores indicate more severe symptoms. A par. had at least 10 days of diary data in any month to contribute a non-missing weighted mean AUC of daily values; otherwise the weighted mean for that month were considered missing. A mixed effects model in a Bayesian framework with repeated measures were performed on the EXACT-PRO monthly weighted mean AUC data. The posterior mean and corresponding 95 percent credible interval were calculated. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | ITT Population | Posted | Mean | Standard Deviation | Score on a scale | Up to Day 392 in Part B |
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| Secondary | Time to First HCRU COPD Exacerbation in Part B | HCRU COPD exacerbations are defined as moderate or severe exacerbations based on requirement of new prescription antibiotics or oral corticosteroids, hospitalization or emergency room visits for management of COPD exacerbation. The time to the first on-treatment HRCU exacerbation were summarized by treatment group. It was analyzed using a Bayesian Cox proportional hazards model. The hazard ratio for the danirixin vs. placebo comparison, along with 95 percent credible interval, was derived, with terms for treatment group, smoking status and country. Posterior probabilities of the ratio of the percentage of par. with an HCRU exacerbation, adjusted for time to first exacerbation, in the danirixin group relative to the placebo group were calculated. 1 par. was excluded from analysis. | ITT Population | Posted | Mean | Standard Deviation | Days | Up to Day 392 in Part B |
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| Secondary | Time to First EXACT-PRO Event in Part B | The hazard ratio for the DNX versus placebo comparison, along with 95% credible interval and posterior probability was derived and a Bayesian Cox proportional hazards model was used for statistical analysis. The analysis was performed on ITT Population. One participant was excluded from analysis. | ITT Population | Posted | Mean | Standard Deviation | Days | Up to Day 392 in Part B |
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| Secondary | Assessment of Duration of EXACT-PRO Events in Part B | Duration is the length of time in days from onset to recovery. It was calculated as the difference in days between day of onset and day of recovery. Onset of event was identified as either an increase in EXACT-PRO score of >=12 points above the par. current mean Baseline for 2 consecutive days, with Day 1 of the 2 days serving as Day 1 onset of the event, or an increase of >=9 points above the par. current mean Baseline for 3 consecutive days, with Day 1 of the 3 days serving as Day 1 onset of the event. Duration was 3-day rolling average was used, which was initiated on Day 1 of onset and ended on Day 1 of Recovery. Recovery was defined as the first day in which par. experienced a persistent, sustained improvement in their condition i.e. decrease in the rolling average EXACT-PRO total score >=9 point from the maximum observed value (highest rolling average EXACT-PRO total score observed the first 14 days of the event) during the first 14 days of an event that is sustained for 7 days. | ITT Population | Posted | Mean | Standard Deviation | Days | Up to Day 392 in Part B |
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| Secondary | Assessment of Severity of EXACT-PRO Events in Part B | EXACT-PRO tool was used to measure severity of COPD exacerbations in participants. Severity was indicated by the maximum EXACT-PRO total score during the course of event (from day of onset to day of recovery). | ITT Population | Posted | Mean | Standard Deviation | Score on a scale | Up to Day 392 in Part B |
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| Secondary | Monthly Weighted Means of EXACT-RS Domain Scores in Part B | EXACT-RS is a tool which consists of 11 items from the 14 item EXACT-PRO instrument, intended to capture information related to the respiratory symptoms of COPD. EXACT-RS domains included breathlessness, cough and chest symptoms. The EXACT-RS has a scoring range of 0-40, higher scores indicate more severe symptoms. A par. had at least 10 days of diary data in any month to contribute a non-missing weighted mean AUC of daily values; otherwise the weighted mean for that month were considered missing. A mixed effects model in a Bayesian framework with repeated measures were performed. The posterior mean and corresponding 95 percent credible interval were calculated. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | ITT Population | Posted | Mean | Standard Deviation | Score on a scale | Up to Day 392 in Part B |
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| Secondary | Change From Baseline for COPD Assessment Test (CAT) at the Indicated Time Points in Part B | The CAT is a validated, 8 item questionnaire which has been developed designed to measure overall COPD-related health status for the initial assessment and longitudinal follow up of par. with COPD. Participants completed each question by rating their experience on a 6 point scale ranging from 0 (no impairment) to 5 (maximum impairment) with a total scoring range of 0 - 40. CAT was assessed at Baseline (Day 1), Day 28, Day 112, Day 168, Day 280 and Day 364 where Baseline was considered as score on Day 1. The change from Baseline was calculated by subtracting the Baseline values from the individual post-randomization values. Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | ITT Population | Posted | Mean | Standard Deviation | Score on a scale | Up to Day 392 in Part B |
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| Secondary | Number of Participants With Physician's Global Assessment (PGA) Readings in Part B | The PGA is a single item clinician reported outcome measure assessing the overall severity of COPD. Physicians rated disease severity on a four point scale ranging from 1-4 (1=mild, 2=moderate, 3=severe, 4=very severe) at Week 0, 4, 8, 16, 24, 40 and 52. Baseline was considered as score on Day 1. A categorical summary of PGA is presented by treatment and visit.Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | ITT Population | Posted | Number | Participants | Up to Day 392 in Part B |
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| Secondary | Number of Participants With Patient Global Rating of Severity (PGRS) Score in Part B | PGRS is a single global question and was asked to participants to rate their COPD severity on a four point scale ranging from 1-4 (1=mild, 2=moderate, 3=severe, 4=very severe). Participants completed PGRS at Week 0, 4, 8, 16, 24, 40 and 52. Baseline was considered as score on Day 1. A categorical summary of PGRS is presented by treatment and visit.Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | ITT Population | Posted | Number | Participants | Up to Day 392 in Part B |
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| Secondary | Number of Participants With Patient Global Impression of Change (PGIC)Score in Part B | Participants completed a PGIC questions at Week 4, 8, 16, 24, 40 and 52. Response options were on a 7 point Likert scale ranging from much better to much worse. PGIC was re-coded from a categorical to numerical value prior to analysis as: much worse = -3, worse = -2, slightly worse = -1, no change = 0, slightly better = 1, better = 2, much better = 3.A categorical summary of PGIC is presented by treatment and visit.Only those participants with data available at the specified time points were analyzed (represented by n=X, X in the category titles). | ITT Population | Posted | Number | Participants | Up to Day 392 in Part B |
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On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the start of the study treatment up to Day 28 in Part A and up to Day 392 in Part B.
On treatment SAEs and non-serious AEs were reported for the All Subjects Population.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
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| EG000 | DNX 50 mg | Participants received one immediate release tablet of danirixin (DNX) 50 mg BID with food and water for 2 weeks. Participants were permitted to continue taking inhaled maintenance medications. Rescue medications for acute symptoms were also permitted (e.g. short acting bronchodilators). | 1 | 9 | 5 | 9 | ||
| EG001 | Placebo | Participants received one tablet of placebo twice daily with food and water for 52 weeks. It was administered on top of the participant's current standard of care. Participants were permitted to continue taking inhaled maintenance medications. Rescue medications for acute symptoms were also permitted (e.g. short acting bronchodilators). | 10 | 48 | 25 | 48 | ||
| EG002 | DNX 75 mg | Participants received one immediate release tablet of danirixin (DNX) 75 mg BID with food and water for 52 weeks. It was administered on top of the participant's current standard of care. Participants were permitted to continue taking inhaled maintenance medications. Rescue medications for acute symptoms were also permitted (e.g. short acting bronchodilators). | 10 | 45 | 25 | 45 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Osteoarthritis | Musculoskeletal and connective tissue disorders | MedDRA 19.0 | Systematic Assessment |
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| Chronic obstructive pulmonary disease | Respiratory, thoracic and mediastinal disorders | MedDRA 19.0 | Systematic Assessment |
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| Hypoxia | Respiratory, thoracic and mediastinal disorders | MedDRA 19.0 | Systematic Assessment |
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| Pneumothorax | Respiratory, thoracic and mediastinal disorders | MedDRA 19.0 | Systematic Assessment |
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| Sleep apnoea syndrome | Respiratory, thoracic and mediastinal disorders | MedDRA 19.0 | Systematic Assessment |
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| Vocal cord leukoplakia | Respiratory, thoracic and mediastinal disorders | MedDRA 19.0 | Systematic Assessment |
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| Atrial fibrillation | Cardiac disorders | MedDRA 19.0 | Systematic Assessment |
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| Atrioventricular block complete | Cardiac disorders | MedDRA 19.0 | Systematic Assessment |
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| Cardiac arrest | Cardiac disorders | MedDRA 19.0 | Systematic Assessment |
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| Coronary artery stenosis | Cardiac disorders | MedDRA 19.0 | Systematic Assessment |
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| Myocardial infarction | Cardiac disorders | MedDRA 19.0 | Systematic Assessment |
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| Ventricular fibrillation | Cardiac disorders | MedDRA 19.0 | Systematic Assessment |
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| Cholangitis sclerosing | Hepatobiliary disorders | MedDRA 19.0 | Systematic Assessment |
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| Cholecystitis acute | Hepatobiliary disorders | MedDRA 19.0 | Systematic Assessment |
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| Cholelithiasis | Hepatobiliary disorders | MedDRA 19.0 | Systematic Assessment |
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| Cholestasis | Hepatobiliary disorders | MedDRA 19.0 | Systematic Assessment |
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| Drug-induced liver injury | Hepatobiliary disorders | MedDRA 19.0 | Systematic Assessment |
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| Hepatic failure | Hepatobiliary disorders | MedDRA 19.0 | Systematic Assessment |
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| Pneumonia | Infections and infestations | MedDRA 19.0 | Systematic Assessment |
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| Cholangitis infective | Infections and infestations | MedDRA 19.0 | Systematic Assessment |
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| Staphylococcal infection | Infections and infestations | MedDRA 19.0 | Systematic Assessment |
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| Craniocerebral injury | Injury, poisoning and procedural complications | MedDRA 19.0 | Systematic Assessment |
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| Foreign body | Injury, poisoning and procedural complications | MedDRA 19.0 | Systematic Assessment |
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| Gastrointestinal haemorrhage | Gastrointestinal disorders | MedDRA 19.0 | Systematic Assessment |
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| Subileus | Gastrointestinal disorders | MedDRA 19.0 | Systematic Assessment |
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| Hypokalaemia | Metabolism and nutrition disorders | MedDRA 19.0 | Systematic Assessment |
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| Obesity | Metabolism and nutrition disorders | MedDRA 19.0 | Systematic Assessment |
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| Arthritis | Musculoskeletal and connective tissue disorders | MedDRA 19.0 | Systematic Assessment |
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| Gallbladder adenoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 19.0 | Systematic Assessment |
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| Non-small cell lung cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 19.0 | Systematic Assessment |
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| Anaemia | Blood and lymphatic system disorders | MedDRA 19.0 | Systematic Assessment |
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| Pain | General disorders | MedDRA 19.0 | Systematic Assessment |
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| Blood sodium decreased | Investigations | MedDRA 19.0 | Systematic Assessment |
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| Brain injury | Nervous system disorders | MedDRA 19.0 | Systematic Assessment |
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| Device loosening | Product Issues | MedDRA 19.0 | Systematic Assessment |
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| Fall | Injury, poisoning and procedural complications | MedDRA 19.0 | Systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Nausea | Gastrointestinal disorders | MedDRA 19.0 | Systematic Assessment |
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| Fatigue | General disorders | MedDRA 19.0 | Systematic Assessment |
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| Malaise | General disorders | MedDRA 19.0 | Systematic Assessment |
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| Nasopharyngitis | Infections and infestations | MedDRA 19.0 | Systematic Assessment |
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| Headache | Nervous system disorders | MedDRA 19.0 | Systematic Assessment |
| |
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 19.0 | Systematic Assessment |
| |
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA 19.0 | Systematic Assessment |
| |
| Hyperhidrosis | Respiratory, thoracic and mediastinal disorders | MedDRA 19.0 | Systematic Assessment |
| |
| Abdominal pain upper | Gastrointestinal disorders | MedDRA 19.0 | Systematic Assessment |
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| Diarrhoea | General disorders | MedDRA 19.0 | Systematic Assessment |
| |
| Cystitis | Infections and infestations | MedDRA 19.0 | Systematic Assessment |
| |
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 19.0 | Systematic Assessment |
|
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.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| GSK Response Center | GlaxoSmithKline | 866-435-7343 |
| ID | Term |
|---|---|
| D029424 | Pulmonary Disease, Chronic Obstructive |
| ID | Term |
|---|---|
| D008173 | Lung Diseases, Obstructive |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
Not provided
Not provided
| ID | Term |
|---|---|
| C581951 | danirixin |
Not provided
Not provided
Not provided
| Physician Decision |
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| Withdrawal by Subject |
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| Male |
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| White - White/Caucasian/European Heritage |
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| DNX 75 mg |
Participants received one immediate release tablet of danirixin (DNX) 75 mg BID with food and water for 52 weeks. It was administered on top of the participant's current standard of care. Participants were permitted to continue taking inhaled maintenance medications. Rescue medications for acute symptoms were also permitted (e.g. short acting bronchodilators). |
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Participants received one immediate release tablet of danirixin (DNX) 75 mg BID with food and water for 52 weeks. It was administered on top of the participant's current standard of care. Participants were permitted to continue taking inhaled maintenance medications. Rescue medications for acute symptoms were also permitted (e.g. short acting bronchodilators). |
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Participants received one immediate release tablet of danirixin (DNX) 75 mg BID with food and water for 52 weeks. It was administered on top of the participant's current standard of care. Participants were permitted to continue taking inhaled maintenance medications. Rescue medications for acute symptoms were also permitted (e.g. short acting bronchodilators). |
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| Participants |
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Participants received one immediate release tablet of danirixin (DNX) 75 mg BID with food and water for 52 weeks. It was administered on top of the participant's current standard of care. Participants were permitted to continue taking inhaled maintenance medications. Rescue medications for acute symptoms were also permitted (e.g. short acting bronchodilators). |
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| Participants |
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