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

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ClinicalTrials.gov Identifier: NCT03034967
Recruitment Status : Completed
First Posted : January 27, 2017
Last Update Posted : October 9, 2018
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

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

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 626 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

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.




Primary Outcome Measures :
  1. Change from baseline in respiratory symptoms measured by Evaluating Respiratory Symptoms in COPD (E-RS) [ Time Frame: Baseline and Day 168 ]
    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. 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.

  2. Number of participants with any adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Up to Day 196 ]
    AE is any untoward medical occurrence in a subject, 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 or any other situation according to medical or scientific judgment will be categorized as SAE.

  3. Number of participants with abnormal clinical chemistry as a measure of safety [ Time Frame: Up to Day 196 ]
    Blood samples will be collected to measure clinical chemistry parameters such as blood urea nitrogen, creatinine, glucose (fasting), potassium, chloride, bicarbonate, sodium, calcium, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, direct bilirubin, total protein, and albumin.

  4. Number of participants with abnormal hematological parameters as a measure of safety [ Time Frame: Up to Day 196 ]
    Blood samples will be collected to measure hematological parameters such as, platelet count, Red blood cell (RBC), count, hemoglobin, hematocrit, RBC Indices, Mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), white blood cells (WBC) with differential counts (neutrophils, lymphocytes, monocytes, eosinophils, and basophils).

  5. Number of participants with abnormal electrocardiogram (ECG) assessment [ Time Frame: Up to Day 168 ]
    Triplicate 12-lead ECG will be obtained to measure PR, QRS, QT, and Corrected QT intervals.

  6. Number of participants with abnormal blood pressure assessment [ Time Frame: Up to Day 168 ]
    Systolic and diastolic blood pressure will be measured in triplicate in semi-supine position after 5 minutes rest.

  7. Number of participants with abnormal pulse rate measurement [ Time Frame: Up to Day 168 ]
    Pulse rate will be measured in triplicate in semi-supine position after 5 minutes rest.

  8. Number of participants with abnormal body temperature [ Time Frame: Up to Day 168 ]
    Body temperature will be measured in semi-supine position after 5 minutes rest.

  9. Number of participants with abnormal respiratory rate [ Time Frame: Up to Day 168 ]
    Body temperature will be measured in semi-supine position after 5 minutes rest.


Secondary Outcome Measures :
  1. Number of participants with Healthcare Resource Utilization (HCRU)-defined COPD exacerbations [ Time Frame: Up to Day 196 ]
    Participants with moderate or severe COPD exacerbations will be analyzed

  2. Responder analysis of E-RS [ Time Frame: Up to Day 168 ]
    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. 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.

  3. Number of Exacerbations of Chronic Pulmonary Disease tool (EXACT) defined events [ Time Frame: Up to Day 196 ]
    Exacerbations of Chronic Pulmonary Disease tool (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.

  4. Time to first EXACT event [ Time Frame: Up to Day 168 ]
    EXACT events will be determined based on pre-defined changes in total EXACT scores.

  5. EXACT event severity [ Time Frame: Up to Day 168 ]
    Exacerbations of Chronic Pulmonary Disease tool (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.

  6. EXACT event duration for all events [ Time Frame: Up to Day 168 ]
    EXACT is 14 item PRO instrument designed to capture occurrence, frequency, severity and duration of the exacerbations of disease in participants with COPD.

  7. Time to first HCRU-defined COPD exacerbation [ Time Frame: Up to Day 196 ]
    Time to first HCRU exacerbation will be defined from the date of randomization.

  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 emergency room visit or extended observation.

  9. HCRU-defined exacerbation duration [ Time Frame: Up to Day 196 ]
    The duration of HCRU exacerbation will be determined.

  10. Change From Baseline in St. George's Respiratory Questionnaire for COPD Patients (SGRQ-C) Total Score [ Time Frame: Baseline and Day 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.

  11. SGRQ responder analysis [ Time Frame: Up to Day 168 ]
    Responder analysis will be performed to determine the proportion of participants achieving at least a 4 point change from their baseline score.

  12. Change for baseline COPD Assessment Test (CAT) total score [ Time Frame: Baseline and Day 168 ]
    The CAT is an 8 item questionnaire that measures health status of participants with COPD. Participants will complete each question by rating their experience on a 6 point scale ranging from 0 to 5 with a total scoring range of 0-40; higher scores indicate worse health status.

  13. CAT responder analysis [ Time Frame: Up to Day 168 ]
    Responder analysis will be performed to determine the proportion of participants achieving at least a 2 point change from their baseline score.

  14. Forced Expiratory Volume in one second (FEV1) as a lung function assessment [ Time Frame: Up to Day 168 ]
    Spirometric analysis is done to determine FEV1.

  15. Percent Predicted FEV1 as a lung function assessment [ Time Frame: Up to Day 168 ]
    Spirometric analysis is done to determine FEV1.

  16. Forced Vital Capacity (FVC) as a lung function assessment [ Time Frame: Up to Day 168 ]
    Spirometric analysis is done to determine FVC.

  17. FEV1/FVC ratio as a lung function assessment [ Time Frame: Up to Day 168 ]
    Spirometric analysis is done to determine FEV1 and FVC.

  18. Use of rescue medication [ Time Frame: Up to Day 168 ]
    Rescue medication use will be assessed via e-diary and metered dose inhaler (MDI) sensor.

  19. Participant experience of physical activity measured using PROactive physical activity in COPD (C-PPAC) questionnaire [ Time Frame: Up to Day 168 ]
    C-PPAC is a 12 item questionnaire. The PROactive tools are scored from 0 to 100 with higher scores indicating greater disease impact. It will be implemented in a subset of approximately 50% of participants.

  20. Area under the curve (AUC) from time zero to 12 hours of Danirixin in whole blood [ Time Frame: Pre-dose, and post-dose at 0.5, 1, 2, 4, 6, 8, 10, 12 hours ]
    Blood samples will be collected from the subject.

  21. Concentration maximum (Cmax) of Danirixin in whole blood [ Time Frame: Pre-dose, and post-dose at 0.5, 1, 2, 4, 6, 8, 10, 12 hours ]
    Blood samples will be collected from the subject.

  22. Time to reach maximum plasma concentration (tmax) of Danirixin in whole blood [ Time Frame: Pre-dose, and post-dose at 0.5, 1, 2, 4, 6, 8, 10, 12 hours ]
    Blood samples will be collected from the subject.



Information from the National Library of Medicine

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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.

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


  Show 69 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline

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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT03034967     History of Changes
Other Study ID Numbers: 205724
First Posted: January 27, 2017    Key Record Dates
Last Update Posted: October 9, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Chronic Disease
Respiratory Tract Diseases
Disease Attributes
Pathologic Processes