Back to resultsA Pilot Study of Danirixin for Disease Progression in Chronic Obstructive Pulmonary Disease (COPD)
Primary Purpose
Pulmonary Disease, Chronic Obstructive
Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Danirixin 35 mg tablets
Placebo
Metered dose inhaler (MDI) sensor device
Rescue medication
Sponsored by
About this trial
This is an interventional treatment trial for Pulmonary Disease, Chronic Obstructive focused on measuring HRQoL, Disease Progression, Danirixin, COPD
Eligibility Criteria
Inclusion Criteria:
- Subject must be 40 to 76 years of age inclusive, at the time of signing the informed consent.
- At the screening visit, the subject must have an FEV1 >40 percent of the predicted normal.
- Subjects with a prior history of asthma are eligible if they have a current diagnosis of COPD.
- Body weight >=45 kilogram (kg).
- A male subject 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 subject is eligible to participate if she is not pregnant, not breastfeeding, and not a woman of childbearing potential (WOCBP).
- Capable of giving signed informed consent, which includes compliance with the requirements and restrictions for this study.
Exclusion Criteria:
- Diagnosis of other clinically relevant lung disease (other than COPD), e.g. sarcoidosis, tuberculosis, pulmonary fibrosis, severe bronchiectasis or lung cancer.
- COPD due to alpha-1-antitrypsin deficiency.
- Pulse oximetry <88 percent at rest at screening. Subjects should be tested while breathing room air. However, subjects 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 < 4Liter/minute and screening oximetry is measured while on their usual settings.
- Less than 14 days have elapsed from completion of a course of antibiotics or oral corticosteroids for a recent COPD exacerbation.
- Subjects with a peripheral blood neutrophil count <1 x 10^9/Liter.
- Diagnosis of pneumonia (chest X-ray or computerized tomography [CT] confirmed) within the 3 months prior to screening.
- Chest X-ray (posterior with lateral) or CT scan reveals evidence of a clinically significant abnormality not believed to be due to the presence of COPD (historic data up to 1 year may be used).
- History or current evidence of clinically significant renal disease, diabetes mellitus/metabolic syndrome, hypertension, or any other clinically significant cardiovascular, neurological, immunological, endocrine, or hematological abnormality 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 subjects at risk through study participation, or which would affect the safety analysis or other analysis if the disease/condition exacerbated during the study.
- 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 of GlaxoSmithKline (GSK) medical monitor, contraindicates their participation.
- Current of chronic history of liver disease, or know 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 subject's medical history and exclude subjects who would be at undue risk by participating in the trial. An abnormal and clinically significant finding that would preclude a subject from entering the trial is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the following:
Atrial fibrillation (AF) with rapid ventricular rate >120 beats per minute (bpm), Sustained or non-sustained ventricular tachycardia (VT), Second-degree heat block Mobitz type II and third degree heart block (unless pacemaker or defibrillator has been implanted, or; QT interval corrected for heart rate per Friderica formula (QTcF) >=500 milliseconds (msec) in subjects with QRS <120 msec and QTcF >=530 msec in subjects 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 cytochrome P450 3A4 (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; BCRP 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). Subjects 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) >2 times upper limit of normal (ULN); bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent).
- 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.
- Subjects who have taken part in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to screening or subjects who plan to enter the acute phase of a pulmonary rehabilitation program during the study. Subjects 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.
- In the opinion of the Investigator, any subject who is unable to read and/or would not be able to complete study related materials.
- 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.
Sites / Locations
- GSK Investigational Site
- GSK Investigational Site
- GSK Investigational Site
- GSK Investigational Site
- GSK Investigational Site
- GSK Investigational Site
- GSK Investigational Site
- GSK Investigational Site
- GSK Investigational Site
- GSK Investigational Site
- GSK Investigational Site
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Subjects receiving danirixin
Subjects receiving placebo
Arm Description
Following screening and assessment of rescue medication use, subjects will receive one tablet of danirixin 35 mg (as hydrobromide hemihydrate salt) orally twice daily with food for 52 weeks during treatment period. Study treatment will be dispensed to subjects at the study visits.
Following screening and assessment of rescue medication use, subjects will receive one tablet of placebo 35 mg orally twice daily with food for 52 weeks during treatment period. Placebo will be dispensed to subjects at the study visits.
Outcomes
Primary Outcome Measures
Rate of Decline in Forced Expiratory Volume in One Second (FEV1)
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. The effect of treatment on decline of post bronchodilator FEV1 recorded during the treatment period was analyzed using a repeated measures random coefficients model with covariates of treatment group, age, sex, smoking status, baseline FEV1, body mass index (BMI), study day and the treatment group by study day interaction. The adjusted mean and standard error for rate of decline in FEV1 have been presented.
Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Total Score (Derived From SGRQ-Chronic Obstructive Pulmonary Disease Specific Tool [SGRQ-C])
The SGRQ-C is a disease-specific questionnaire designed to measure the impact of respiratory disease and its treatment on a COPD participant's health-related quality of life (HRQoL). SGRQ-C total score was converted to SGRQ total score according to manual. The SGRQ Questionnaire is a well-established, self-completed tool, with 50 questions comprising three domains; Symptoms, Activity, and Impacts scores (each ranging from 0 to 100). SGRQ total score was calculated by summing weights from all positive items, divided by sum of weights for all items in SGRQ questionnaire and multiplying by 100. The SGRQ total score ranges from 0 to 100, with 0 implying the best possible health status and 100 implying worst possible health status. Baseline was defined as the score recorded prior to dosing on Day 1. Change from Baseline was calculated by subtracting Baseline value from the post dose visit value.
Secondary Outcome Measures
Number of Participants With Adverse Events (AEs) and Serious Adverse Event (SAEs)
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 was categorized as SAE. Number of participants with AEs and SAEs are summarized.
Number of Participants With Worst Case Hematology Results by Potential Clinical Importance (PCI) Criteria
Blood samples were collected. PCI ranges were, basophils(%):5x(high), eosinophils(%):2x(high), hematocrit(proportion of red blood cells in blood):0.50x(low) or 1.30x(high), hemoglobin (grams per liter):0.85x(low) or 1.20x(high), lymphocytes(%):0.80x(low) or 1.20x(high), mean corpuscle hemoglobin(picogram):0.85x(low) or 1.20x(high), mean corpuscle hemoglobin concentration(gram per deciliter):0.85x(low) or 1.10x(high), mean corpuscle volume(femtoliter):0.25x(low) or 2.00x(high), monocytes(%):0.80x(low) or 1.60x(high), platelet(x10^9 cells per liter[cells/L]):0.90x(low) or 1.10x(high), Red Blood Cell(x10^12 cells/L):0.93x(low) or 1.07x(high), neutrophil(%):0.65x(low) or 1.50x(high), White Blood Cell(x10^9 cells/L):0.70x(low) or 1.60x(high). Participants were counted in the worst case if their laboratory value changes to low/within range or no change/high and were counted in the within range if their value was unchanged. Limits with 'x' are multipliers of central laboratory normal range.
Number of Participants With Worst Case Clinical Chemistry Results by PCI Criteria
Blood samples for clinical chemistry parameters were collected at indicated time points. PCI ranges were, calcium (millimoles per liter [mmol/L]): 0.85x (low) or 1.08x (high), bicarbonate (mmol/L): <18 (low) or >32 (high), chloride (mmol/L): 0.90x (low) or 1.10x (high), creatinine (micromoles per liter[µmol/L]): 1.30x (high), glucose(mmol/L): <0.6x (low) or >4x (high), potassium (mmol/L): 0.75x (low) or 1.30x (high), sodium (mmol/L): 0.80x (low) or 1.15x (high), total protein (milligram per deciliter[mg/dL]): 1.25x (high), blood urea nitrogen(BUN) (mmol/L): 0.70x (low) or 1.60x(high). Participants were counted in the worst case if their laboratory value changes to low, or within range or no change, or high. Participants were counted in within range if their value was unchanged. Limits with 'x' are multipliers of central laboratory normal range.
Number of Participants With Worst Case Liver Function Tests Results by PCI Criteria
Blood samples for liver function tests were collected at indicated time points. PCI ranges were, alanine aminotransferase (ALT) (units per liter[U/L]): >=3x upper limit of normal (ULN) (high), alkaline phosphatase (alk phosp) (U/L): >=2x ULN (high), aspartate amino transferase (AST) (U/L): >=3x ULN (high), direct bilirubin (µmol/L): >=2x ULN (high), total bilirubin (µmol/L): >=2x ULN (high). Participants were counted in the worst case if their laboratory value changes to low, or within range or no change, or high. Participants were counted in within range if their value was unchanged. Limits with 'x' are multipliers of central laboratory normal range.
Number of Participants With Abnormalities in Urinalysis Data
Urine samples were planned to be collected to analyze the following parameters: specific gravity, pH, glucose, protein, blood and ketones. This analysis was planned but data was not collected, as study was terminated pre-maturely.
Change From Baseline in Electrocardiogram (ECG) Parameters: Heart Rate
12-lead ECG was obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT (QTc) intervals. Baseline was defined as the value obtained at pre-dose on Day 1. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Change From Baseline in ECG Parameters: PR, QRS, QT and QTc Intervals
12-lead ECG was obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. Baseline was defined as the value obtained at pre-dose on Day 1. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Number of Participants With Worst-case Vital Signs Results by PCI Criteria
Vital signs included systolic blood pressure (SBP) and diastolic blood pressure (DBP), heart rate and respiratory rate. Vital signs were measured in a semi-supine position after 5 minutes rest. PCI ranges were, SBP (millimeters of mercury): <90 (low) or >160 (high), DBP (millimeters of mercury): <40 (low) or >110 (high), heart rate (beats per minute): <35 (low) or >120 (high), respiration rate (breaths per minute): <8 (low) or >30 (high). Participants were counted in the worst-case category that their value changes to (low, within range or no change, or high), unless there was no change in their category. Participants whose value category were unchanged (high to high), or whose value became within range, were recorded in the 'to within range or no change' category.
C-reactive Protein (CRP) Levels (Safety Biomarker) After Administration of Danirixin
Peripheral venous blood samples were planned to be collected and tested for biomarker that was indicative of inflammation (CRP). This analysis was planned but data was not collected, as the study was terminated pre-maturely.
Time to First Healthcare Resource Utilization (HCRU) Chronic Obstructive Pulmonary Disease (COPD) Exacerbation
An exacerbation of COPD was defined by a worsening of symptoms requiring additional treatment or hospitalization. The date of onset of COPD exacerbations were planned to be recorded. This analysis was planned but data was not collected, as the study was terminated pre-maturely.
Change From Baseline in FEV1
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. FEV1 measurements were collected using a spirometer. Baseline was defined as the measurement performed prior to the first dose on Day 1. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Number of SGRQ Responders
Response was defined as a SGRQ total score of 4 units below Baseline or lower. The SGRQ Questionnaire is a well-established, self-completed tool, with 50 questions comprising three domains; Symptoms, Activity, and Impacts scores (each ranging from 0 to 100). SGRQ total score was calculated by summing weights from all positive items, divided by sum of weights for all items in SGRQ questionnaire and multiplying by 100. The SGRQ total score ranges from 0 to 100, with 0 implying the best possible health status and 100 implying worst possible health status. Number of SGRQ responders are presented.
Change From Baseline in SGRQ Symptoms Score
The SGRQ Questionnaire is a well-established, self-completed tool, comprising of 50 questions with 76 weighted responses designed to measure Quality of Life in participants with diseases of airway obstruction. It consists of two parts; Part 1 produces the symptoms score and Part 2 produces the activity and impacts score. SGRQ symptoms score was calculated by summing weights from all positive items in symptoms score component, divided by sum of weights for all items in symptoms score component and multiplying by 100. The SGRQ symptoms score ranges from 0 to 100, with 0 implying the best possible health status and 100 implying worst possible health status. Baseline was defined as the score recorded prior to dosing on Day 1. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Change From Baseline in SGRQ Activity Score
The SGRQ Questionnaire is a well-established, self-completed tool, comprising of 50 questions with 76 weighted responses designed to measure quality of life in participants with diseases of airway obstruction. It consists of two parts; Part 1 produces the symptoms score and Part 2 produces the activity and impacts score. SGRQ activity score was calculated by summing weights from all positive items in activity score component, divided by sum of weights for all items in activity score component and multiplying by 100. The SGRQ activity score ranges from 0 to 100, with 0 implying the best possible health status and 100 implying worst possible health status. Baseline was defined as the score recorded prior to dosing on Day 1. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Change From Baseline in SGRQ Impacts Score
The SGRQ Questionnaire is a well-established, self-completed tool, comprising of 50 questions with 76 weighted responses designed to measure Quality of Life in participants with diseases of airway obstruction. It consists of two parts; Part 1 produces the symptoms score and Part 2 produces the activity and impacts score. SGRQ impacts score was calculated by summing weights from all positive items in impacts score component, divided by sum of weights for all items in impacts score component and multiplying by 100. The SGRQ impacts score ranges from 0 to 100, with 0 implying the best possible health status and 100 implying worst possible health status. Baseline was defined as the score recorded prior to dosing on Day 1. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Change From Baseline in COPD Assessment Test (CAT) Score
The COPD Assessment Test (CAT) is a short and simple participant completed questionnaire which was developed for use in routine clinical practice to measure the health status of participants with COPD. The CAT is an 8-item questionnaire suitable for completion by all participants diagnosed with COPD. Participants rated their experience on a 6-point scale, ranging from 0 (maximum impairment) to 5 (no impairment). A total CAT score was calculated by summing the non-missing scores of the eight items with a scoring range of 0-40. Higher scores indicated greater disease impact. Baseline was defined as the score recorded prior to dosing on Day 1. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Change From Baseline in Mean Percentage Rescue Free Days Using Diary Data in 4-week Intervals
Participants were instructed to complete the daily diary in the evening to collect the number of puffs of rescue medications over each 24-hour period. The maximum number of puffs of rescue medications use were counted for the day and were used to determine if it was a recue-free day. A rescue-free day was defined as a day where the total number of puffs were 0. The 4-weekly means were calculated and presented. Baseline was defined as the mean number of puffs of rescue medication per day from the latest (7 days before study treatment start date and date of Screening) to the day before study treatment start date. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Change From Baseline in Mean Number of Puffs Per Day of Rescue Medication Using Diary Data in 4-week Intervals
Participants were instructed to complete the daily diary in the evening to collect the number of puffs of rescue medications over each 24-hour period. The maximum number of puffs of rescue medication use were counted for the day and were used to determine if it was a recue-free day. A rescue-free day was defined as a day where the total number of puffs were 0. The 4-weekly means were calculated and presented. Baseline was defined as the mean number of puffs of rescue medication per day from the latest (7 days before study treatment start date and date of Screening) to the day before study treatment start date. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03170232
Brief Title
A Pilot Study of Danirixin for Disease Progression in Chronic Obstructive Pulmonary Disease (COPD)
Official Title
A Randomized, Double-blind, Sponsor Open, Placebo-controlled, 52 Week Study Evaluating the Effect of Danirixin (GSK1325756) on Lung Function and Health Related Quality of Life in Participants With Mild to Moderate Chronic Obstructive Pulmonary Disease (COPD)
Study Type
Interventional
2. Study Status
Record Verification Date
July 2020
Overall Recruitment Status
Terminated
Why Stopped
Terminated based on lack of efficacy seen in participants taking danirixin in dose ranging study and Sponsor decision to stop development of danirixin for COPD
Study Start Date
October 16, 2017 (Actual)
Primary Completion Date
November 15, 2018 (Actual)
Study Completion Date
November 15, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
GlaxoSmithKline
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
Yes
Data Monitoring Committee
No
5. Study Description
Brief Summary
This is a pilot study to investigate the effect of danirixin hydrobromide 35 milligram (mg) tablets on lung function and health related quality of life (HRQoL) in subjects with mild to moderate airflow obstruction and a demonstrated history of decline in forced expiratory volume in one second (FEV1). Specifically, this study aims to assess whether or not danirixin has the potential to impact disease progression in subjects with a COPD progression score indicating they are likely to decline based on 5 year data from a COPDGene study and support the conduct of a larger Phase III study for disease progression. Subjects will receive either placebo or danirixin 35 mg tablets (as hydrobromide hemihydrate salt) twice daily for 52 weeks (12months). Study subjects will continue with their standard of care inhaled medications (i.e. long acting bronchodilators with or without inhaled corticosteroids) while receiving study treatment. This study will be an ancillary study within the COPDGene study investigating the enrichment strategy for assessing disease progression. Potential subjects most likely to decline from the well established COPDGene cohort, will be based on data collected over the initial 5 year period. With the use of an enriched population, it is anticipated that one year of treatment will be sufficient to detect a trend in altering disease progression. Approximately 130 subjects will be screened to enroll 100 subjects in this study. The data from this study will provide useful information in determining whether to progress to a Phase III study to explore an indication for slowing disease progression.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Disease, Chronic Obstructive
Keywords
HRQoL, Disease Progression, Danirixin, COPD
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
54 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Subjects receiving danirixin
Arm Type
Experimental
Arm Description
Following screening and assessment of rescue medication use, subjects will receive one tablet of danirixin 35 mg (as hydrobromide hemihydrate salt) orally twice daily with food for 52 weeks during treatment period. Study treatment will be dispensed to subjects at the study visits.
Arm Title
Subjects receiving placebo
Arm Type
Placebo Comparator
Arm Description
Following screening and assessment of rescue medication use, subjects will receive one tablet of placebo 35 mg orally twice daily with food for 52 weeks during treatment period. Placebo will be dispensed to subjects at the study visits.
Intervention Type
Drug
Intervention Name(s)
Danirixin 35 mg tablets
Intervention Description
Danirixin 35 mg (as hydrobromide hemihydrate salt) is a white film coated oval shaped tablet. It will be provided in a labeled high-density polyethylene (HDPE) bottle with desiccant.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo is a white film coated oval shaped tablet. It will be provided in a labeled HDPE bottle with desiccant.
Intervention Type
Device
Intervention Name(s)
Metered dose inhaler (MDI) sensor device
Intervention Description
MDI sensor devices will be fitted onto rescue medication MDI devices to electronically record rescue medication usage.
Intervention Type
Drug
Intervention Name(s)
Rescue medication
Intervention Description
Subjects may continue to use rescue medication(s) via their usual route. Allowed medications are: short acting beta agonists (SABA) (e.g., albuterol/salbutamol); short acting muscarinic antagonists (SAMA) (e.g., ipratropium); short acting combination (SABA/SAMA) bronchodilators, (e.g. Duoneb, Combivent)
Primary Outcome Measure Information:
Title
Rate of Decline in Forced Expiratory Volume in One Second (FEV1)
Description
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. The effect of treatment on decline of post bronchodilator FEV1 recorded during the treatment period was analyzed using a repeated measures random coefficients model with covariates of treatment group, age, sex, smoking status, baseline FEV1, body mass index (BMI), study day and the treatment group by study day interaction. The adjusted mean and standard error for rate of decline in FEV1 have been presented.
Time Frame
Up to Week 52
Title
Change From Baseline in St. George's Respiratory Questionnaire (SGRQ) Total Score (Derived From SGRQ-Chronic Obstructive Pulmonary Disease Specific Tool [SGRQ-C])
Description
The SGRQ-C is a disease-specific questionnaire designed to measure the impact of respiratory disease and its treatment on a COPD participant's health-related quality of life (HRQoL). SGRQ-C total score was converted to SGRQ total score according to manual. The SGRQ Questionnaire is a well-established, self-completed tool, with 50 questions comprising three domains; Symptoms, Activity, and Impacts scores (each ranging from 0 to 100). SGRQ total score was calculated by summing weights from all positive items, divided by sum of weights for all items in SGRQ questionnaire and multiplying by 100. The SGRQ total score ranges from 0 to 100, with 0 implying the best possible health status and 100 implying worst possible health status. Baseline was defined as the score recorded prior to dosing on Day 1. Change from Baseline was calculated by subtracting Baseline value from the post dose visit value.
Time Frame
Baseline (Day 1 pre-dose), Weeks 12, 24 and 32
Secondary Outcome Measure Information:
Title
Number of Participants With Adverse Events (AEs) and Serious Adverse Event (SAEs)
Description
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 was categorized as SAE. Number of participants with AEs and SAEs are summarized.
Time Frame
Up to Week 52
Title
Number of Participants With Worst Case Hematology Results by Potential Clinical Importance (PCI) Criteria
Description
Blood samples were collected. PCI ranges were, basophils(%):5x(high), eosinophils(%):2x(high), hematocrit(proportion of red blood cells in blood):0.50x(low) or 1.30x(high), hemoglobin (grams per liter):0.85x(low) or 1.20x(high), lymphocytes(%):0.80x(low) or 1.20x(high), mean corpuscle hemoglobin(picogram):0.85x(low) or 1.20x(high), mean corpuscle hemoglobin concentration(gram per deciliter):0.85x(low) or 1.10x(high), mean corpuscle volume(femtoliter):0.25x(low) or 2.00x(high), monocytes(%):0.80x(low) or 1.60x(high), platelet(x10^9 cells per liter[cells/L]):0.90x(low) or 1.10x(high), Red Blood Cell(x10^12 cells/L):0.93x(low) or 1.07x(high), neutrophil(%):0.65x(low) or 1.50x(high), White Blood Cell(x10^9 cells/L):0.70x(low) or 1.60x(high). Participants were counted in the worst case if their laboratory value changes to low/within range or no change/high and were counted in the within range if their value was unchanged. Limits with 'x' are multipliers of central laboratory normal range.
Time Frame
Up to Week 52
Title
Number of Participants With Worst Case Clinical Chemistry Results by PCI Criteria
Description
Blood samples for clinical chemistry parameters were collected at indicated time points. PCI ranges were, calcium (millimoles per liter [mmol/L]): 0.85x (low) or 1.08x (high), bicarbonate (mmol/L): <18 (low) or >32 (high), chloride (mmol/L): 0.90x (low) or 1.10x (high), creatinine (micromoles per liter[µmol/L]): 1.30x (high), glucose(mmol/L): <0.6x (low) or >4x (high), potassium (mmol/L): 0.75x (low) or 1.30x (high), sodium (mmol/L): 0.80x (low) or 1.15x (high), total protein (milligram per deciliter[mg/dL]): 1.25x (high), blood urea nitrogen(BUN) (mmol/L): 0.70x (low) or 1.60x(high). Participants were counted in the worst case if their laboratory value changes to low, or within range or no change, or high. Participants were counted in within range if their value was unchanged. Limits with 'x' are multipliers of central laboratory normal range.
Time Frame
Up to Week 52
Title
Number of Participants With Worst Case Liver Function Tests Results by PCI Criteria
Description
Blood samples for liver function tests were collected at indicated time points. PCI ranges were, alanine aminotransferase (ALT) (units per liter[U/L]): >=3x upper limit of normal (ULN) (high), alkaline phosphatase (alk phosp) (U/L): >=2x ULN (high), aspartate amino transferase (AST) (U/L): >=3x ULN (high), direct bilirubin (µmol/L): >=2x ULN (high), total bilirubin (µmol/L): >=2x ULN (high). Participants were counted in the worst case if their laboratory value changes to low, or within range or no change, or high. Participants were counted in within range if their value was unchanged. Limits with 'x' are multipliers of central laboratory normal range.
Time Frame
Up to Week 52
Title
Number of Participants With Abnormalities in Urinalysis Data
Description
Urine samples were planned to be collected to analyze the following parameters: specific gravity, pH, glucose, protein, blood and ketones. This analysis was planned but data was not collected, as study was terminated pre-maturely.
Time Frame
Up to Week 52
Title
Change From Baseline in Electrocardiogram (ECG) Parameters: Heart Rate
Description
12-lead ECG was obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT (QTc) intervals. Baseline was defined as the value obtained at pre-dose on Day 1. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Time Frame
Baseline (Day 1 pre-dose), Weeks 4, 12 and 24
Title
Change From Baseline in ECG Parameters: PR, QRS, QT and QTc Intervals
Description
12-lead ECG was obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. Baseline was defined as the value obtained at pre-dose on Day 1. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Time Frame
Baseline (Day 1 pre-dose), Weeks 4, 12 and 24
Title
Number of Participants With Worst-case Vital Signs Results by PCI Criteria
Description
Vital signs included systolic blood pressure (SBP) and diastolic blood pressure (DBP), heart rate and respiratory rate. Vital signs were measured in a semi-supine position after 5 minutes rest. PCI ranges were, SBP (millimeters of mercury): <90 (low) or >160 (high), DBP (millimeters of mercury): <40 (low) or >110 (high), heart rate (beats per minute): <35 (low) or >120 (high), respiration rate (breaths per minute): <8 (low) or >30 (high). Participants were counted in the worst-case category that their value changes to (low, within range or no change, or high), unless there was no change in their category. Participants whose value category were unchanged (high to high), or whose value became within range, were recorded in the 'to within range or no change' category.
Time Frame
Up to Week 52
Title
C-reactive Protein (CRP) Levels (Safety Biomarker) After Administration of Danirixin
Description
Peripheral venous blood samples were planned to be collected and tested for biomarker that was indicative of inflammation (CRP). This analysis was planned but data was not collected, as the study was terminated pre-maturely.
Time Frame
Up to Week 52
Title
Time to First Healthcare Resource Utilization (HCRU) Chronic Obstructive Pulmonary Disease (COPD) Exacerbation
Description
An exacerbation of COPD was defined by a worsening of symptoms requiring additional treatment or hospitalization. The date of onset of COPD exacerbations were planned to be recorded. This analysis was planned but data was not collected, as the study was terminated pre-maturely.
Time Frame
Up to Week 52
Title
Change From Baseline in FEV1
Description
FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. FEV1 measurements were collected using a spirometer. Baseline was defined as the measurement performed prior to the first dose on Day 1. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Time Frame
Baseline (Day 1 pre-dose), Weeks 2, 4, 8, 12, 16, 20, 24, 32 and 40
Title
Number of SGRQ Responders
Description
Response was defined as a SGRQ total score of 4 units below Baseline or lower. The SGRQ Questionnaire is a well-established, self-completed tool, with 50 questions comprising three domains; Symptoms, Activity, and Impacts scores (each ranging from 0 to 100). SGRQ total score was calculated by summing weights from all positive items, divided by sum of weights for all items in SGRQ questionnaire and multiplying by 100. The SGRQ total score ranges from 0 to 100, with 0 implying the best possible health status and 100 implying worst possible health status. Number of SGRQ responders are presented.
Time Frame
Weeks 12, 24 and 32
Title
Change From Baseline in SGRQ Symptoms Score
Description
The SGRQ Questionnaire is a well-established, self-completed tool, comprising of 50 questions with 76 weighted responses designed to measure Quality of Life in participants with diseases of airway obstruction. It consists of two parts; Part 1 produces the symptoms score and Part 2 produces the activity and impacts score. SGRQ symptoms score was calculated by summing weights from all positive items in symptoms score component, divided by sum of weights for all items in symptoms score component and multiplying by 100. The SGRQ symptoms score ranges from 0 to 100, with 0 implying the best possible health status and 100 implying worst possible health status. Baseline was defined as the score recorded prior to dosing on Day 1. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Time Frame
Baseline (Day 1 pre-dose), Weeks 12, 24 and 32
Title
Change From Baseline in SGRQ Activity Score
Description
The SGRQ Questionnaire is a well-established, self-completed tool, comprising of 50 questions with 76 weighted responses designed to measure quality of life in participants with diseases of airway obstruction. It consists of two parts; Part 1 produces the symptoms score and Part 2 produces the activity and impacts score. SGRQ activity score was calculated by summing weights from all positive items in activity score component, divided by sum of weights for all items in activity score component and multiplying by 100. The SGRQ activity score ranges from 0 to 100, with 0 implying the best possible health status and 100 implying worst possible health status. Baseline was defined as the score recorded prior to dosing on Day 1. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Time Frame
Baseline (Day 1 pre-dose), Weeks 12, 24 and 32
Title
Change From Baseline in SGRQ Impacts Score
Description
The SGRQ Questionnaire is a well-established, self-completed tool, comprising of 50 questions with 76 weighted responses designed to measure Quality of Life in participants with diseases of airway obstruction. It consists of two parts; Part 1 produces the symptoms score and Part 2 produces the activity and impacts score. SGRQ impacts score was calculated by summing weights from all positive items in impacts score component, divided by sum of weights for all items in impacts score component and multiplying by 100. The SGRQ impacts score ranges from 0 to 100, with 0 implying the best possible health status and 100 implying worst possible health status. Baseline was defined as the score recorded prior to dosing on Day 1. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Time Frame
Baseline (Day 1 pre-dose), Weeks 12, 24 and 32
Title
Change From Baseline in COPD Assessment Test (CAT) Score
Description
The COPD Assessment Test (CAT) is a short and simple participant completed questionnaire which was developed for use in routine clinical practice to measure the health status of participants with COPD. The CAT is an 8-item questionnaire suitable for completion by all participants diagnosed with COPD. Participants rated their experience on a 6-point scale, ranging from 0 (maximum impairment) to 5 (no impairment). A total CAT score was calculated by summing the non-missing scores of the eight items with a scoring range of 0-40. Higher scores indicated greater disease impact. Baseline was defined as the score recorded prior to dosing on Day 1. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Time Frame
Baseline (Day 1 pre-dose), Weeks 12, 24 and 32
Title
Change From Baseline in Mean Percentage Rescue Free Days Using Diary Data in 4-week Intervals
Description
Participants were instructed to complete the daily diary in the evening to collect the number of puffs of rescue medications over each 24-hour period. The maximum number of puffs of rescue medications use were counted for the day and were used to determine if it was a recue-free day. A rescue-free day was defined as a day where the total number of puffs were 0. The 4-weekly means were calculated and presented. Baseline was defined as the mean number of puffs of rescue medication per day from the latest (7 days before study treatment start date and date of Screening) to the day before study treatment start date. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Time Frame
Baseline (Day 1 pre-dose), Weeks 1-4, Weeks 5-8, Weeks 9-12, Weeks 13-16, Weeks 17-20, Weeks 21-24, Weeks 25-28, Weeks 29-32, Weeks 33-36, Weeks 37-40, Weeks 41-44 and Weeks 45-48
Title
Change From Baseline in Mean Number of Puffs Per Day of Rescue Medication Using Diary Data in 4-week Intervals
Description
Participants were instructed to complete the daily diary in the evening to collect the number of puffs of rescue medications over each 24-hour period. The maximum number of puffs of rescue medication use were counted for the day and were used to determine if it was a recue-free day. A rescue-free day was defined as a day where the total number of puffs were 0. The 4-weekly means were calculated and presented. Baseline was defined as the mean number of puffs of rescue medication per day from the latest (7 days before study treatment start date and date of Screening) to the day before study treatment start date. Change from Baseline was calculated by subtracting Baseline value from the post-dose visit value.
Time Frame
Baseline (Day 1 pre-dose), Weeks 1-4, Weeks 5-8, Weeks 9-12, Weeks 13-16, Weeks 17-20, Weeks 21-24, Weeks 25-28, Weeks 29-32, Weeks 33-36, Weeks 37-40, Weeks 41-44 and Weeks 45-48
10. Eligibility
Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
76 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Subject must be 40 to 76 years of age inclusive, at the time of signing the informed consent.
At the screening visit, the subject must have an FEV1 >40 percent of the predicted normal.
Subjects with a prior history of asthma are eligible if they have a current diagnosis of COPD.
Body weight >=45 kilogram (kg).
A male subject 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 subject is eligible to participate if she is not pregnant, not breastfeeding, and not a woman of childbearing potential (WOCBP).
Capable of giving signed informed consent, which includes compliance with the requirements and restrictions for this study.
Exclusion Criteria:
Diagnosis of other clinically relevant lung disease (other than COPD), e.g. sarcoidosis, tuberculosis, pulmonary fibrosis, severe bronchiectasis or lung cancer.
COPD due to alpha-1-antitrypsin deficiency.
Pulse oximetry <88 percent at rest at screening. Subjects should be tested while breathing room air. However, subjects 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 < 4Liter/minute and screening oximetry is measured while on their usual settings.
Less than 14 days have elapsed from completion of a course of antibiotics or oral corticosteroids for a recent COPD exacerbation.
Subjects with a peripheral blood neutrophil count <1 x 10^9/Liter.
Diagnosis of pneumonia (chest X-ray or computerized tomography [CT] confirmed) within the 3 months prior to screening.
Chest X-ray (posterior with lateral) or CT scan reveals evidence of a clinically significant abnormality not believed to be due to the presence of COPD (historic data up to 1 year may be used).
History or current evidence of clinically significant renal disease, diabetes mellitus/metabolic syndrome, hypertension, or any other clinically significant cardiovascular, neurological, immunological, endocrine, or hematological abnormality 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 subjects at risk through study participation, or which would affect the safety analysis or other analysis if the disease/condition exacerbated during the study.
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 of GlaxoSmithKline (GSK) medical monitor, contraindicates their participation.
Current of chronic history of liver disease, or know 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 subject's medical history and exclude subjects who would be at undue risk by participating in the trial. An abnormal and clinically significant finding that would preclude a subject from entering the trial is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the following:
Atrial fibrillation (AF) with rapid ventricular rate >120 beats per minute (bpm), Sustained or non-sustained ventricular tachycardia (VT), Second-degree heat block Mobitz type II and third degree heart block (unless pacemaker or defibrillator has been implanted, or; QT interval corrected for heart rate per Friderica formula (QTcF) >=500 milliseconds (msec) in subjects with QRS <120 msec and QTcF >=530 msec in subjects 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 cytochrome P450 3A4 (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; BCRP 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). Subjects 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) >2 times upper limit of normal (ULN); bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent).
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.
Subjects who have taken part in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to screening or subjects who plan to enter the acute phase of a pulmonary rehabilitation program during the study. Subjects 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.
In the opinion of the Investigator, any subject who is unable to read and/or would not be able to complete study related materials.
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
GSK Clinical Trials
Organizational Affiliation
GlaxoSmithKline
Official's Role
Study Director
Facility Information:
Facility Name
GSK Investigational Site
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States
Facility Name
GSK Investigational Site
City
San Diego
State/Province
California
ZIP/Postal Code
92103-8415
Country
United States
Facility Name
GSK Investigational Site
City
Torrance
State/Province
California
ZIP/Postal Code
90502
Country
United States
Facility Name
GSK Investigational Site
City
Denver
State/Province
Colorado
ZIP/Postal Code
80206
Country
United States
Facility Name
GSK Investigational Site
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52243
Country
United States
Facility Name
GSK Investigational Site
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21224
Country
United States
Facility Name
GSK Investigational Site
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109-5360
Country
United States
Facility Name
GSK Investigational Site
City
Saint Paul
State/Province
Minnesota
ZIP/Postal Code
55101
Country
United States
Facility Name
GSK Investigational Site
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19140
Country
United States
Facility Name
GSK Investigational Site
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
Facility Name
GSK Investigational Site
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
IPD for this study will be made available via the Clinical Study Data Request site.
IPD Sharing Time Frame
IPD is available via the Clinical Study Data Request site (click on the link provided below)
IPD Sharing 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.
IPD Sharing URL
https://clinicalstudydatarequest.com/Posting.aspx?ID=20388
Learn more about this trial
A Pilot Study of Danirixin for Disease Progression in Chronic Obstructive Pulmonary Disease (COPD)
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