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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03034967
Recruitment Status : Completed
First Posted : January 27, 2017
Results First Posted : November 29, 2019
Last Update Posted : October 28, 2020
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

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

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

Study Design
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Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 614 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: Randomised, Double-Blind (Sponsor Open), Placebo-Controlled, Multicentre, Dose Ranging Study to Evaluate the Efficacy and Safety of Danirixin Tablets Administered Twice Daily Compared With Placebo for 24 Weeks in Adult Participants With Chronic Obstructive Pulmonary Disease (COPD)
Actual Study Start Date : April 25, 2017
Actual Primary Completion Date : October 5, 2018
Actual Study Completion Date : October 5, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: COPD Lung Diseases

Arms and Interventions
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Arm Intervention/treatment
Experimental: Danirixin 5 mg
Eligible participants will receive danirixin 5 mg tablet with food twice daily along with standard care of treatment for 24 weeks.
 Drug: Danirixin
Danirixin is available as 5, 10, 25, 35 and 50 mg white, film-coated, oval or round shaped tablets for oral administration.

Drug: Standard of care
Participants will continue with their standard of care inhaled medications (i.e. long acting bronchodilators with or without inhaled corticosteroids) during the study treatment.

Drug: Rescue medication
Participants will continue to use rescue medication(s). The following rescue medications may be used: short acting beta agonists, short acting muscarinic antagonists, or short acting combination bronchodilators.
Experimental: Danirixin 10 mg
Eligible participants will receive danirixin 10 mg tablet with food twice daily along with standard care of treatment for 24 weeks.
 Drug: Danirixin
Danirixin is available as 5, 10, 25, 35 and 50 mg white, film-coated, oval or round shaped tablets for oral administration.

Drug: Standard of care
Participants will continue with their standard of care inhaled medications (i.e. long acting bronchodilators with or without inhaled corticosteroids) during the study treatment.

Drug: Rescue medication
Participants will continue to use rescue medication(s). The following rescue medications may be used: short acting beta agonists, short acting muscarinic antagonists, or short acting combination bronchodilators.
Experimental: Danirixin 25 mg
Eligible participants will receive danirixin 25 mg tablet with food twice daily along with standard care of treatment for 24 weeks.
 Drug: Danirixin
Danirixin is available as 5, 10, 25, 35 and 50 mg white, film-coated, oval or round shaped tablets for oral administration.

Drug: Standard of care
Participants will continue with their standard of care inhaled medications (i.e. long acting bronchodilators with or without inhaled corticosteroids) during the study treatment.

Drug: Rescue medication
Participants will continue to use rescue medication(s). The following rescue medications may be used: short acting beta agonists, short acting muscarinic antagonists, or short acting combination bronchodilators.
Experimental: Danirixin 35 mg
Eligible participants will receive danirixin 35 mg tablet with food twice daily along with standard care of treatment for 24 weeks.
 Drug: Danirixin
Danirixin is available as 5, 10, 25, 35 and 50 mg white, film-coated, oval or round shaped tablets for oral administration.

Drug: Standard of care
Participants will continue with their standard of care inhaled medications (i.e. long acting bronchodilators with or without inhaled corticosteroids) during the study treatment.

Drug: Rescue medication
Participants will continue to use rescue medication(s). The following rescue medications may be used: short acting beta agonists, short acting muscarinic antagonists, or short acting combination bronchodilators.
Experimental: Danirixin 50 mg
Eligible participants will receive danirixin 50 mg tablet with food twice daily along with standard care of treatment for 24 weeks.
 Drug: Danirixin
Danirixin is available as 5, 10, 25, 35 and 50 mg white, film-coated, oval or round shaped tablets for oral administration.

Drug: Standard of care
Participants will continue with their standard of care inhaled medications (i.e. long acting bronchodilators with or without inhaled corticosteroids) during the study treatment.

Drug: Rescue medication
Participants will continue to use rescue medication(s). The following rescue medications may be used: short acting beta agonists, short acting muscarinic antagonists, or short acting combination bronchodilators.
Placebo Comparator: Placebo
Eligible participants will receive placebo tablet with food twice daily along with standard care of treatment for 24 weeks.
 Drug: Danirixin matching placebo
Danirixin matching placebo will be available as white, film-coated, oval or round shaped tablets for oral administration.

Drug: Standard of care
Participants will continue with their standard of care inhaled medications (i.e. long acting bronchodilators with or without inhaled corticosteroids) during the study treatment.

Drug: Rescue medication
Participants will continue to use rescue medication(s). The following rescue medications may be used: short acting beta agonists, short acting muscarinic antagonists, or short acting combination bronchodilators.


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

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

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

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

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

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

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

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

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


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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   40 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  • Participants must be aged between 40 to 80 years of age inclusive, at the time of signing the informed consent.
  • Participants who have COPD (post bronchodilator FEV1/FVC ratio <0.7 and FEV1% predicted >=40%) based on American Thoracic Society (ATS)/European Respiratory Society (ERS) current guidelines. Participants with a historical diagnosis of asthma may be included so long as they have a current diagnosis of COPD.
  • History of respiratory symptoms including chronic cough, mucus hypersecretion, and dyspnea on most days for at least the previous 3 months prior to screening.
  • Participants with a documented history of COPD exacerbation(s) in the 12 months prior to study participation (screening) meeting at least one of the following criteria: >=2 COPD exacerbations resulting in prescription for antibiotics and/or oral corticosteroids or hospitalization or extended observation in a hospital emergency room or outpatient center; 1 COPD exacerbation resulting in prescription for antibiotics and/or oral corticosteroids of hospitalization or extended observation in a hospital emergency room or outpatient center and a plasma fibrinogen concentration at screening >=3 grams/liter (300 milligram/deciliter)
  • Current and former smokers with a cigarette smoking history of >=10 pack years (1 pack year = 20 cigarettes smoked per day for 1 year or equivalent). Current smokers are defined as those who are currently smoking cigarettes (i.e. have smoked at least one cigarette daily or most days for the month prior to Visit 1). Former smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1.
  • Participants must have the ability and willingness to use an electronic diary (log pad) on a daily basis.
  • Body weight >=45 kilogram (kg)
  • Male or female: A male participant must agree to use contraception during the treatment period and for at least 60 hours after the last dose of study treatment, corresponding to approximately 6 half-lives (which is the time needed to eliminate any teratogenic study treatment) and to refrain from donating sperm during this period; A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) OR A WOCBP who agrees to follow the contraceptive guidance during the treatment period and for at least 60 hours after the last dose of study treatment.
  • Capable of giving signed informed consent.

Exclusion Criteria

  • Diagnosis of other clinically relevant lung diseases (other than COPD), e.g. sarcoidosis, tuberculosis, pulmonary fibrosis, severe bronchiectasis or lung cancer.
  • Alpha-1-antitrypsin deficiency as the underlying cause of COPD
  • Pulse oximetry <88% at rest at screening. Participants should be tested while breathing room air. However, participants living at high altitudes (above 5000 feet or 1500 meters above sea level) who are receiving supplemental oxygen can be included provided they are receiving the equivalent of <4 liter per minute (L/min) and screening pulse oximetry is measured while on their usual oxygen settings.
  • Less than 14 days have elapsed from the completion of a course of antibiotics or oral corticosteroids for a recent COPD exacerbation.
  • A peripheral blood neutrophil count <1.5 x 10^9/L.
  • Diagnosis of pneumonia (chest X-ray or CT confirmed) within the 3 months prior to screening.
  • Chest x-ray (posterior-anterior with lateral) or CT scan reveals evidence of a clinically significant abnormality not believed to be due to the presence of COPD (historic results up to 1 year prior to screening may be used). For sites in Germany: If a chest x-ray (or CT scan) within 1 year prior to screening is not available, approval to conduct a diagnostic chest x-ray will need to be obtained from the Federal Office of Radiation Protection (BfS).
  • History or current evidence of other clinically significant medical condition that is uncontrolled on permitted therapies. Significant is defined as any disease that, in the opinion of the Investigator, would put the safety of the participant at risk through study participation, or that would affect the safety analysis or other analysis if the disease/condition worsened during the study.
  • Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
  • Abnormal and clinically significant 12-lead ECG finding. The investigator will determine the clinical significance of each abnormal ECG finding in relation to the participant's medical history and exclude participants who would be at undue risk by participating in the study. An abnormal and clinically significant finding that would preclude a participant from entering the study is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the following: atrial fibrillation with rapid ventricular rate >120 beats per minute (bpm); sustained or non-sustained ventricular tachycardia; second degree heart block Mobitz type II and third degree heart block (unless pacemaker or defibrillator has been implanted); Corrected QT Interval using Fridericia formula (QTcF) >=500 millisecond (msec) in participants with QRS <120 msec and QTcF >=530 msec in participants with QRS >=120 msec.
  • Previous lung surgery (e.g. lobectomy, pneumonectomy) or lung volume reduction procedure.
  • Current or expected chronic use of macrolide antibiotics during the study period for the prevention of COPD exacerbations. Examples of chronic use include, but are not limited to, daily or two to three times per week use for at least 3 months.
  • Oral or injectable CYP3A4 or breast cancer resistance protein (BRCP) substrates with a narrow therapeutic index (CYP3A4 substrates include, but are not limited to, alfenatil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, and theophylline; BRCP substrates include, but are not limited to, topotecan.) The Investigator should consult with the Medical Monitor if necessary.
  • Current or expected use of phosphodiesterase-4 inhibitors (e.g. roflumilast). Participants currently receiving roflumilast may be included if they are able to discontinue use from 30 days prior to screening through the completion of the follow up visit.
  • Participation in a previous clinical trial and has received an investigational product within any of the following time periods prior to the first dosing day in the current study: 30 days, 5 half lives, or twice the duration of the biological effect of the investigational product (whichever is longer).
  • Participation in a previous clinical trial with danirixin within 1 year prior to the first dosing day in the current study
  • Exposure to more than four investigational products within 1 year prior to the first dosing day in the current study.
  • Alanine transferase (ALT) >2x upper limit of normal (ULN); bilirubin > 1.5xULN (isolated bilirubin > 1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
  • A positive test for human immunodeficiency virus (HIV) antibody
  • A positive pre-study hepatitis B surface antigen or positive hepatitis C antibody result within 3 months prior to screening.
  • Pulmonary rehabilitation: Participants who have taken part in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to screening or participants who plan to enter the acute phase of a pulmonary rehabilitation program during the study. Participants who are in the maintenance phase of a pulmonary rehabilitation program are not excluded.
  • A history of allergy or hypersensitivity to any of the ingredients in the study treatment.
  • A known or suspected history of alcohol or drug abuse within the 2 years prior to screening.
  • Inability to read: in the opinion of the Investigator, any participant who is unable to read and/or would not be able to complete study related materials.
  • Affiliation with the study site: study investigators, sub-investigators, study coordinators, employees of a study investigator, sub-investigator or study site, or immediate family member of any of the above that are involved with the study.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03034967


Locations
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Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline
  Study Documents (Full-Text)

Documents provided by GlaxoSmithKline:
Statistical Analysis Plan  [PDF] October 30, 2018
Study Protocol  [PDF] October 31, 2017

More Information
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Publications:

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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT03034967    
Other Study ID Numbers: 205724
2016-003675-21 ( EudraCT Number )
First Posted: January 27, 2017    Key Record Dates
Results First Posted: November 29, 2019
Last Update Posted: October 28, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: IPD for this study is available via the Clinical Study Data Request site.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: IPD is available via the Clinical Study Data Request site (copy the URL below to your browser)
Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
URL: https://www.clinicalstudydatarequest.com/Posting.aspx?ID=20593

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by GlaxoSmithKline:
HCRU exacerbations
SGRQ
CXCR2 antagonist
 GSK1325756
Danirixin
COPD
Additional relevant MeSH terms:
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Lung Diseases
Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Respiratory Tract Diseases