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Investigation of Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Clinical Efficacy of Oral Danirixin in Symptomatic COPD Subjects With Mild to Moderate Airflow Limitation at Risk for Exacerbations

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ClinicalTrials.gov Identifier: NCT02130193
Recruitment Status : Completed
First Posted : May 5, 2014
Results First Posted : May 18, 2017
Last Update Posted : July 2, 2017
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Tracking Information
First Submitted Date  ICMJE December 19, 2013
First Posted Date  ICMJE May 5, 2014
Results First Submitted Date  ICMJE April 4, 2017
Results First Posted Date  ICMJE May 18, 2017
Last Update Posted Date July 2, 2017
Actual Study Start Date  ICMJE February 13, 2014
Actual Primary Completion Date August 29, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 13, 2017)
  • Number of Participants With Any Adverse Event (AE) and, Serious Adverse Event (SAE) in Part A [ Time Frame: Up to Day 28 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.
  • Number of Participants With Any AE and SAE in Part B [ Time Frame: Up to Day 392 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.
  • 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 [ Time Frame: Up to Day 28 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.
  • 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 [ Time Frame: Up to Day 392 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).
  • Number of Participants With Abnormal 12-lead Electrocardiogram (ECG) in Part A [ Time Frame: Up to Day 28 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.
  • Number of Participants With Abnormal 12-lead ECG in Part B [ Time Frame: Up to Day 392 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).
  • Number of Participants With Hematology Values of Potential Clinical Importance in Part A [ Time Frame: Up to Day 28 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.
  • Number of Participants With Hematology Values of Potential Clinical Importance in Part B [ Time Frame: Up to Day 392 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).
  • Number of Participants With Clinical Chemistry Values of Potential Clinical Importance in Part A [ Time Frame: Up to Day 28 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.
  • Number of Participants With Clinical Chemistry Values of Potential Clinical Importance in Part B [ Time Frame: Up to Day 392 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).
  • Number of Participants With Urinalysis Dipstick Results in Part A [ Time Frame: Up to Day 28 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).
  • Number of Participants With Urinalysis Dipstick Results in Part B [ Time Frame: Up to Day 392 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).
  • Change From Baseline in Urine Power of Hydrogen (pH) at Day 14 in Part A [ Time Frame: Up to Day 28 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.
  • Change From Baseline in Urine pH in Part B [ Time Frame: Up to Day 392 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).
  • Change From Baseline in Urine Specific Gravity of Urine in Part A [ Time Frame: Up to Day 28 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.
  • Change From Baseline in Urine Specific Gravity of Urine in Part B [ Time Frame: Up to Day 392 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.
  • Change From Baseline in Forced Expiratory Volume in One Second (FEV1) and Forced Vital Capacity (FVC) at the Indicated Time Points in Part A [ Time Frame: Up to Day 28 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.
  • Change From Baseline in FEV1 and FVC at the Indicated Time Points in Part B [ Time Frame: Up to Day 392 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).
  • Maximum Observed Plasma Concentration (Cmax) of Danirixin in Part A [ Time Frame: 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 ]
    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.
  • Time of Occurrence of Cmax (Tmax) of Danirixin in Part A [ Time Frame: 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 ]
    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.
  • Area Under the Blood Concentration-time Curve (AUC) Over Dosing Interval (AUC[0-12]) of Danirixin in Part A [ Time Frame: 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 ]
    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.
  • Number of Health Care Resource Utilization (HCRU) Defined COPD Exacerbations Per Year in Part B [ Time Frame: Up to Day 392 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.
  • Monthly Weighted Means of Exacerbations of Chronic Pulmonary Disease Tool-respiratory Symptoms (EXACT-RS) Total Score in Part B [ Time Frame: Up to Day 392 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).
Original Primary Outcome Measures  ICMJE
 (submitted: May 1, 2014)
  • Safety and tolerability of danirixin compared with placebo- Part A and B [ Time Frame: Part A-Up to Day 28. Part B-Up to Day 392 ]
    Safety and tolerability assessments will include adverse events (AEs), Vital Signs, Electrocardiogram (ECG), Clinical laboratory evaluations (hematology, clinical chemistry, urinalysis) and Lung Function assessment using spirometry
  • Pharmacokinetic (PK) parameters for danirixin- Part A [ Time Frame: Day 1 and Day 14 ]
    PK parameters like maximum observed blood concentration (Cmax), time to Cmax (tmax) and area under the blood concentration-time curve [AUC(0-t)], and apparent terminal phase half-life (t1/2) will be assessed if data permits. Blood sample for PK assessment will be collected at pre-dose, 0.5, 1, 2, 4, 6, 8, 10 and 12 hr on the scheduled visit days
  • Number of subjects with Health Care Resource Utilization (HCRU) defined COPD exacerbations- Part B [ Time Frame: Upto Day 392 ]
    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.
  • Monthly weighted means of Exacerbations of Chronic Pulmonary Disease- Respiratory Symptoms (EXACT-RS)-Part B [ Time Frame: Upto Day 392 ]
    EXACT-RS is a tool which consists of 11 items from the 14 item EXACT- Patient Reported Outcomes (EXACT-PRO) instrument. EXACT-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 EXACT-RS has a scoring range of 0-40, higher scores indicate more severe symptoms.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 7, 2017)
  • Cmax of Danirixin in Part B [ Time Frame: 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 ]
    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).
  • Tmax of Danirixin in Part B [ Time Frame: 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 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).
  • AUC(0-12) of Danirixin in Part B [ Time Frame: 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 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).
  • Number of EXACT-PRO Exacerbations Per Year in Part B [ Time Frame: Up to Day 392 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.
  • Monthly Weighted Means of Exacerbations of EXACT-PRO Total Score in Part B [ Time Frame: Up to Day 392 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).
  • Time to First HCRU COPD Exacerbation in Part B [ Time Frame: Up to Day 392 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.
  • Time to First EXACT-PRO Event in Part B [ Time Frame: Up to Day 392 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.
  • Assessment of Duration of EXACT-PRO Events in Part B [ Time Frame: Up to Day 392 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.
  • Assessment of Severity of EXACT-PRO Events in Part B [ Time Frame: Up to Day 392 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).
  • Monthly Weighted Means of EXACT-RS Domain Scores in Part B [ Time Frame: Up to Day 392 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).
  • Change From Baseline for COPD Assessment Test (CAT) at the Indicated Time Points in Part B [ Time Frame: Up to Day 392 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).
  • Number of Participants With Physician's Global Assessment (PGA) Readings in Part B [ Time Frame: Up to Day 392 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).
  • Number of Participants With Patient Global Rating of Severity (PGRS) Score in Part B [ Time Frame: Up to Day 392 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).
  • Number of Participants With Patient Global Impression of Change (PGIC)Score in Part B [ Time Frame: Up to Day 392 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).
Original Secondary Outcome Measures  ICMJE
 (submitted: May 1, 2014)
  • PK parameters for danirixin- Part B [ Time Frame: Days 1, 28, 56, 168 and 364 ]
    PK parameters like maximum observed blood concentration (Cmax), time to Cmax (tmax) and area under the blood concentration-time curve [AUC(0-t)], and apparent terminal phase half-life (t1/2) will be assessed if data permits. Blood sample for PK assessment will be collected at pre-dose, 0.5, 1, 2, 4, 6, 8, 10 and 12 hr on Day 1 and Day 364. Blood sample for PK assessment will be collected at pre-dose and 2hr on Days 28, 56 and 168.
  • Exacerbations of EXACT-PRO event- Part B [ Time Frame: Upto Day 392 ]
    EXACT-PRO, an Exacerbations of Chronic Pulmonary Disease Tool is a 14 item patient reported outcome instrument designed to capture information on the occurrence, frequency, severity, and duration of exacerbations of disease in patients with COPD. The total score for EXACT-PRO ranges from 0 - 100, higher scores indicate more severe symptoms.
  • EXACT-PRO total score weighted means- Part B [ Time Frame: Upto Day 392 ]
  • Time to first HCRU COPD exacerbation- Part B [ Time Frame: Upto Day 392 ]
  • Time to first moderate HCRU COPD exacerbation- Part B [ Time Frame: Upto Day 392 ]
    A COPD exacerbation is defined as a moderate exacerbation if it requires new prescription for the treatment with antibiotics and/or systemic corticosteroids.
  • Time to first severe HCRU COPD exacerbation- Part B [ Time Frame: Upto Day 392 ]
    A COPD exacerbation defined as a severe exacerbation if it requires hospitalization or emergency room visit
  • Time to first EXACT-PRO event- Part B [ Time Frame: Upto Day 392 ]
  • EXACT-PRO events severity and duration- Part B [ Time Frame: Upto Day 392 ]
  • Monthly weighted mean EXACT-RS domain scores - Part B [ Time Frame: Upto Day 392 ]
    EXACT-RS domains will include breathlessness, cough & sputum, chest symptoms
  • COPD Assessment Test (CAT) - Part B [ Time Frame: Days 1, 28, 112, 168, 280, 364 and between Days 378 and 392 ]
    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 COPD patients. Subjects will complete 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
  • Lung function assessment using spirometry - Part B [ Time Frame: Screening, Days 1, 28, 56, 112, 168, 280, 364 and between Days 378 and 392 ]
    Forced Expiratory Volume in one second (FEV1) and Forced Vital Capacity (FVC) will be measured using spirometry
  • Physician's Global Assessment (PGA) - Part B [ Time Frame: Days 1, 28, 56, 112, 168, 280, 364 and between Days 378 and 392 ]
    PGA is a single item clinician Reported outcome measure to assess the overall severity of COPD. Physicians will rate disease severity on a four point scale (mild, moderate, severe, very severe) at visits 2, 4, 5, 7, 9, 11 and 12 (or early withdrawal)
  • Patient Global Rating of Severity (PGRS)- Part B [ Time Frame: Days 1, 28, 56, 112, 168, 280, 364 and between Days 378 and 392 ]
    PGRS is single global question which will ask patients to rate their COPD severity on a four-point scale (mild, moderate, severe, very severe).
  • Patient Global Impression of Change (PGIC)- Part B [ Time Frame: Days 28, 56, 112, 168, 280, 364 and between Days 378 and 392 ]
    PGIC response options will be on a 7 point Likert scale ranging from much better to much worse
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Investigation of Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Clinical Efficacy of Oral Danirixin in Symptomatic COPD Subjects With Mild to Moderate Airflow Limitation at Risk for Exacerbations
Official Title  ICMJE A Two Part, Phase IIa, Randomized, Placebo-controlled Study To Investigate The Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Clinical Efficacy of Oral Danirixin (GSK1325756) in Symptomatic COPD Subjects With Mild to Moderate Airflow Limitation at Risk for Exacerbations
Brief Summary

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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Pulmonary Disease, Chronic Obstructive
Intervention  ICMJE
  • Drug: Danirixin
    Danirixin is available as 50 or 75 mg white, film coated immediate release tablet.
  • Drug: Placebo
    Subjects will receive danirixin matching placebo
Study Arms  ICMJE
  • Experimental: Part A
    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.
    Intervention: Drug: Danirixin
  • Experimental: Part B
    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.
    Interventions:
    • Drug: Danirixin
    • Drug: Placebo
Publications * 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). pii: 1801020. doi: 10.1183/13993003.01020-2018. Print 2018 Oct.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 23, 2016)
102
Original Estimated Enrollment  ICMJE
 (submitted: May 1, 2014)
110
Actual Study Completion Date  ICMJE August 29, 2016
Actual Primary Completion Date August 29, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Male or female aged between 40 and 70 years of age inclusive, at the time of signing the informed consent
  • Subjects with a documented history of COPD exacerbation(s) in the 12 months prior to study participation 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 or hospitalization or extended observation in a hospital emergency room or outpatient center and a plasma fibrinogen concentration at screening >=3.5 milligram/milliliter (mg/mL)
  • Diagnosis of symptomatic chronic obstructive pulmonary disease with mild to moderate airflow obstruction (COPD-GOLD I or II) for at least 2 years based on American Thoracic Society (ATS)/ European Respiratory Society (ERS) current guidelines or symptoms consistent with COPD for at least 2 years
  • Subjects with a post-bronchodilator FEV1/FVC ratio of < 0.7 and FEV1 >=50% of predicted normal value calculated using National Health and Nutrition Examination Survey (NHANES) III reference equation at Visit 1
  • A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy [for this definition, "documented" refers to the outcome of the investigator's/designee's review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records]; or postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) >40 milli international units/mL (MIU/mL) and estradiol < 40 picogram (pg)/mL (<147 picomole/Liter [pmol/L]) is confirmatory]. Females on hormone replacement therapy (HRT) will not be enrolled in the study.
  • Body weight >=45 kilogram (kg)
  • Current smokers and former smokers with a cigarette smoking history of >=10 pack years (1 pack year =20 cigarettes smoked per day for 1 year or equivalent). Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1
  • Subjects with a history of respiratory symptoms, including chronic cough and/or mucus hypersecretion on most days for at least the previous 3 months prior to Visit 1
  • Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) <2x upper limit of normal (ULN); alkaline phosphatase and bilirubin <=1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
  • Able to perform lung function tests reliably
  • Based on single or averaged corrected QT (QTc) values of triplicate ECGs obtained over a brief recording period: Fridericia-corrected QTc (QTcF) < 450 milliseconds (msec); or QTc < 480 msec in subjects with Bundle Branch Block
  • Subjects must have the ability to use an electronic diary on a daily basis [Part B only]
  • Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form

Exclusion Criteria:

  • Diagnosis of asthma, or other clinically relevant lung disease (other than COPD), e.g. sarcoidosis, tuberculosis, pulmonary fibrosis, severe bronchiectasis or lung cancer; Subject with alpha-1-antitrypsin deficiency as the underlying cause of COPD
  • Pulse Oximetry levels <88% (at rest on room air) at screening
  • Less than 14 days have elapsed from completion of a course of antibiotics or oral corticosteroids for a recent COPD exacerbation.
  • Diagnosis of Pneumonia (chest X-Ray or computed tomography [CT] confirmed) within the last 3 months prior to screening
  • History or current evidence of clinically significant renal disease, diabetes mellitus/metabolic syndrome, hypertension or any other clinically significant cardiovascular, neurological, endocrine, or hematological abnormalities that are uncontrolled on permitted therapy. Significant is defined as any disease that, in the opinion of the Investigator, would put the safety of the subjects at risk through study participation, or which would affect the safety analysis or other analysis if the disease/condition exacerbated during the study.
  • A positive pre-study drug/alcohol screen
  • 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 of screening
  • History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GSK Medical Monitor, contraindicates their participation
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • History of regular alcohol consumption within 6 months of the study defined as: For non United States of America (US) sites: an average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits; For US sites: an average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.
  • Current or expected use of proton pump inhibitors or histamine H2-receptor antagonists during the study period
  • Chest X-ray (posteroanterior with lateral) or CT scan reveals evidence of pneumonia or a clinically significant abnormality not believed to be due to the presence of COPD (historic data up to 1 yr may be used).
  • Subjects with peripheral blood neutrophil count (PBN) <2x10^9/Liter
  • Subject with history of previous lung surgery (e.g. lobectomy, pneumonectomy, or lung volume reduction)
  • Requiring the use of oral or injectable Cytochrome P450 3A4 (CYP3A4) or breast cancer resistance protein (BCRP) substrates with a narrow therapeutic index
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02130193
Other Study ID Numbers  ICMJE 200163
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party GlaxoSmithKline
Study Sponsor  ICMJE GlaxoSmithKline
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: GSK Clinical Trials GlaxoSmithKline
PRS Account GlaxoSmithKline
Verification Date April 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP