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

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)

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.

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.