A Pilot Study of Danirixin for Disease Progression in Chronic Obstructive Pulmonary Disease (COPD)

ID: NCT03170232
Status: Recruiting
Phase: Phase 2
Start Date: October 16, 2017
First Submitted: May 18, 2017
Last Updated: February 22, 2018
Results: N/A
Organization: GlaxoSmithKline
Sponsors & Collaborators: GlaxoSmithKline
Location: United States
Conditions: Pulmonary Disease, Chronic Obstructive
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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.

Detailed Description

Condition or disease Intervention/treatment Phase

Pulmonary Disease, Chronic Obstructive

Drug: Danirixin 35 mg tablets
Other Names
Drug: Placebo
Other Names
Device: Metered dose inhaler (MDI) sensor device
Other Names
Drug: Rescue medication
Other Names
Phase 2

Tracking Information

First Submitted DateMay 18, 2017
Last Update Posted DateFebruary 22, 2018
Actual Start DateOctober 16, 2017
Anticipated Completion DateJune 13, 2019
Actual Primary Completion DateJune 13, 2019
Results First Submitted DateN/A
Received Results Disposit DateN/A

Current Primary Outcome Measures

  • Safety biomarkers as a measure of safety of danirixin [Time Frame: Up to Week 52]

    Peripheral venous blood samples will be collected at Week 0, 24 and 52 and will be tested for biomarkers that are indicative of inflammation (i.e. c-reactive protein) and additional biomarkers thought to play a role in COPD disease progression or to evaluate their association with observed clinical responses to danirixin.

  • Number of subjects with clinically significant electrocardiogram (ECG) findings [Time Frame: Up to Week 52]

    12-lead ECG will be obtained using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and corrected QT (QTc) intervals. 12-lead ECG will be recorded at Screening and at Week 0 (Day 1) in triplicate. A single 12-lead ECG will be recorded at Week 4, 12, 24 and 52.

  • Number of subjects with clinically significant abnormalities in respiratory rate [Time Frame: Up to Week 52]

    A single measurement of respiratory rate will be recorded at Week 0, 4, 12, 24 and 52.

  • Number of subjects with clinically significant abnormalities in pulse rate [Time Frame: Up to Week 52]

    Pulse rate will be measured in a semi-supine position after 5 minutes rest. Three readings will be taken, of which the first reading will be rejected. The second and third readings will be averaged to give the measurement. Pulse rate will be recorded at Week 0, 4, 12, 24 and 52.

  • Number of subjects with clinically significant abnormalities in systolic and diastolic blood pressure [Time Frame: Up to Week 52]

    Systolic and diastolic blood pressure will be measured in a semi-supine position after 5 minutes rest. Three readings will be taken, of which the first reading will be rejected. The second and third readings will be averaged to give the measurement. Systolic and diastolic blood pressure will be recorded at Week 0, 4, 12, 24 and 52.

  • Number of subjects with clinically significant abnormalities in laboratory parameters [Time Frame: Up to Week 52]

    Blood sample (for hematology and clinical chemistry) and urine sample (for urinalysis) will be collected at Week 0, 4, 24 and 52.

  • Number of subjects with any adverse event (AE) and serious adverse event (SAE) [Time Frame: Up to Week 52]

    An AE is any untoward medical occurrence in a subject or clinical investigation 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, 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 subject or may require medical or surgical intervention will be categorized as SAE. Number of subjects with on-treatment AEs or SAEs will be summarized.

  • Change from Baseline in St. George's Respiratory Questionnaire (SGRQ) total score (derived from SGRQ-Chronic Obstructive Pulmonary Disease specific tool [SGRQ-C]) [Time Frame: Up to Week 52]

    The St. George's Respiratory Questionnaire-Chronic Obstructive Pulmonary Disease specific tool is a disease-specific questionnaire designed to measure the impact of respiratory disease and its treatment on HRQoL of subjects with COPD. Overall summary score as well as scores for the individual domains of symptoms, activity and impact will be produced. SGRQ total score will be derived from SGRQ-C at Week 0, 12, 24, 32 and 52.

  • Rate of decline in FEV1 [Time Frame: Up to Week 52]

    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 will be performed in triplicate at Week 0, 2, 4, 8, 12, 16, 20, 24, 32, 40 and 52 in clinic using spirometer. Spirometry will also be performed weekly by the subjects using a mobile spirometer at home.

Original Primary Outcome Measures

Not Available

Current Secondary Outcome Measures

  • Time to first Healthcare Resource Utilization (HCRU) COPD exacerbation [Time Frame: Up to Week 52]

    An exacerbation of COPD is defined by a worsening of symptoms requiring additional treatment or hospitalization. The date of onset and the date of resolution and medications used for the treatment of exacerbations will be recorded.

  • Change from Baseline in FEV1 [Time Frame: Up to Week 52]

    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 will be performed in triplicate at Week 0, 2, 4, 8, 12, 16, 20, 24, 32, 40 and 52 in clinic using spirometer. Spirometry will also be performed weekly by the subjects using a mobile spirometer at home.

  • Number of responders from SGRQ responder analysis [Time Frame: Up to Week 52]

    The St. George's Respiratory Questionnaire is a disease-specific questionnaire designed to measure the impact of respiratory disease and its treatment on HRQoL of subjects with diseases of airways obstruction. SGRQ total score will be derived from SGRQ-C at Week 0, 12, 24, 32 and 52.

  • Assessment of SGRQ domain scores [Time Frame: Up to Week 52]

    Overall summary score as well as scores for the individual domains of symptoms, activity and impacts will be produced. SGRQ total score will be derived from SGRQ-C at Week 0, 12, 24, 32 and 52.

  • Assessment of COPD assessment test (CAT) [Time Frame: Up to Week 52]

    The COPD Assessment Test is a simple questionnaire which has been developed for use in routine clinical practice to measure the health status of subjects with COPD. The CAT is an 8-item questionnaire suitable for completion by all subjects diagnosed with COPD. Subjects will rate their experience on a 6-point scale, ranging from 0 (maximum impairment) to 5 (no impairment) with a scoring range of 0-40. Higher scores indicate greater disease impact. CAT will be assessed at Week 0, 12, 24, 32 and 52.

  • Assessment of rescue medication use [Time Frame: Up to Week 52]

    Use of rescue medication by the subjects will be recorded throughout the treatment duration of 52 weeks.

Original Secondary Outcome Measures

Not Available

Study Design

Brief TitleA Pilot Study of Danirixin for Disease Progression in Chronic Obstructive Pulmonary Disease (COPD)
Official TitleA 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)
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.

Detailed Description

Study TypeInterventional
Study PhasePhase 2
Estimated Enrollment
100
Allocation
Randomized
Interventional Model
Parallel Assignment
Masking
Triple
Primary Purpose
Treatment
Conditions
Pulmonary Disease, Chronic Obstructive
Target Follow-Up Duration N/A
Biospecimen:
N/A
Sampling MethodN/A
Study PopulationN/A
Intervention
Drug: Danirixin 35 mg tablets

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.

Other Names
Drug: Placebo

Placebo is a white film coated oval shaped tablet. It will be provided in a labeled HDPE bottle with desiccant.

Other Names
Device: Metered dose inhaler (MDI) sensor device

MDI sensor devices will be fitted onto rescue medication MDI devices to electronically record rescue medication usage.

Other Names
Drug: Rescue medication

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)

Other Names
Study Groups/Cohorts
Subjects receiving danirixin
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.

Subjects receiving placebo
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.

Study Arms
Experimental Subjects receiving danirixin
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.
Drug : Danirixin 35 mg tablets
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.

Experimental Subjects receiving danirixin
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.
Device : Metered dose inhaler (MDI) sensor device
MDI sensor devices will be fitted onto rescue medication MDI devices to electronically record rescue medication usage.

Experimental Subjects receiving danirixin
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.
Drug : Rescue medication
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)

Placebo Comparator Subjects receiving placebo
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.
Drug : Rescue medication
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)

Placebo Comparator Subjects receiving placebo
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.
Device : Metered dose inhaler (MDI) sensor device
MDI sensor devices will be fitted onto rescue medication MDI devices to electronically record rescue medication usage.

Placebo Comparator Subjects receiving placebo
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.
Drug : Placebo
Placebo is a white film coated oval shaped tablet. It will be provided in a labeled HDPE bottle with desiccant.

Arm Intervention/Treatment
Experimental Subjects receiving danirixin
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.
Drug : Danirixin 35 mg tablets
Experimental Subjects receiving danirixin
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.
Device : Metered dose inhaler (MDI) sensor device
Experimental Subjects receiving danirixin
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.
Drug : Rescue medication
Placebo Comparator Subjects receiving placebo
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.
Drug : Rescue medication
Placebo Comparator Subjects receiving placebo
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.
Device : Metered dose inhaler (MDI) sensor device
Placebo Comparator Subjects receiving placebo
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.
Drug : Placebo

Recruitment Information

Recruitment Status:Recruiting
Enrollment100
Completion DateJune 13, 2019
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.
GenderAll
Age40 Years to 76 Years
Accepts Healthy VolunteersNo
Contacts
Listed Location Countries
United States

Administrative Information

NCT Number:NCT03170232
Other Study ID Numbers
205864
Has Data Monitoring CommitteeNo
U.S. FDA-regulated Product Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: No
IPD Sharing Statement
Not Available
Responsible Party,
Study Sponsor
GlaxoSmithKline
Collaborators
Not Available
Investigators
Study Director
GSK Clinical Trials
GlaxoSmithKline