Investigation of Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Clinical Efficacy of Oral Danirixin in Symptomatic COPD Subjects With Mild to Moderate Airflow Limitation at Risk for Exacerbations
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Pulmonary Disease, Chronic Obstructive
Intervention: Danirixin; Placebo
Intervention description: Danirixin is available as 50 or 75 mg white, film coated immediate release tablet.; Subjects will receive danirixin matching placebo
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 102.0
Sex: All
Minimum age: 40 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Efficacy; Danirixin; EXACT-PRO; COPD; Safety; RD; CXCR2 inhibitor; EXACT-RS; PK; HCRU exacerbations; PD

Summary:

      The aim of this First Time in Patient study is to obtain initial information on the safety,
      tolerability, pharmacokinetics, pharmacodynamics and clinical efficacy of repeat daily
      administration of danirixin in subjects with symptomatic chronic obstructive pulmonary
      disease (COPD) having mild to moderate airflow limitation and are at high risk for future
      COPD exacerbations.

      The study will be conducted in two parts. Part A will be a two week open label, single arm
      study in patients with COPD to obtain pharmacokinetic data and safety information of repeat
      dosing of danirixin in the population of interest. Approximately 10 subjects will be enrolled
      in Part A of the study. Progression to and dose selection for Part B will occur following
      review of the data collected in Part A. Part B will be a 52-week, randomized, double-blind
      (sponsor unblind), placebo-controlled on top of standard of care, parallel group study. Part
      B will evaluate several clinical efficacy assessments related to exacerbations and
      respiratory symptoms. Approximately 100 subjects will be enrolled with a target of 80
      subjects completing 52 weeks of danirixin administration.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male or female aged between 40 and 70 years of age inclusive, at the time of signing
             the informed consent

          -  Subjects with a documented history of COPD exacerbation(s) in the 12 months prior to
             study participation 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 or hospitalization or extended observation in a hospital emergency
             room or outpatient center and a plasma fibrinogen concentration at screening >=3.5
             milligram/milliliter (mg/mL)

          -  Diagnosis of symptomatic chronic obstructive pulmonary disease with mild to moderate
             airflow obstruction (COPD-GOLD I or II) for at least 2 years based on American
             Thoracic Society (ATS)/ European Respiratory Society (ERS) current guidelines or
             symptoms consistent with COPD for at least 2 years

          -  Subjects with a post-bronchodilator FEV1/FVC ratio of < 0.7 and FEV1 >=50% of
             predicted normal value calculated using National Health and Nutrition Examination
             Survey (NHANES) III reference equation at Visit 1

          -  A female subject is eligible to participate if she is of: Non-childbearing potential
             defined as pre-menopausal females with a documented tubal ligation or hysterectomy
             [for this definition, "documented" refers to the outcome of the
             investigator's/designee's review of the subject's medical history for study
             eligibility, as obtained via a verbal interview with the subject or from the subject's
             medical records]; or postmenopausal defined as 12 months of spontaneous amenorrhea [in
             questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH)
             >40 milli international units/mL (MIU/mL) and estradiol < 40 picogram (pg)/mL (<147
             picomole/Liter [pmol/L]) is confirmatory]. Females on hormone replacement therapy
             (HRT) will not be enrolled in the study.

          -  Body weight >=45 kilogram (kg)

          -  Current smokers 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). Former smokers
             are defined as those who have stopped smoking for at least 6 months prior to Visit 1

          -  Subjects with a history of respiratory symptoms, including chronic cough and/or mucus
             hypersecretion on most days for at least the previous 3 months prior to Visit 1

          -  Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) <2x upper limit of
             normal (ULN); alkaline phosphatase and bilirubin <=1.5xULN (isolated bilirubin
             >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)

          -  Able to perform lung function tests reliably

          -  Based on single or averaged corrected QT (QTc) values of triplicate ECGs obtained over
             a brief recording period: Fridericia-corrected QTc (QTcF) < 450 milliseconds (msec);
             or QTc < 480 msec in subjects with Bundle Branch Block

          -  Subjects must have the ability to use an electronic diary on a daily basis [Part B
             only]

          -  Capable of giving written informed consent, which includes compliance with the
             requirements and restrictions listed in the consent form

        Exclusion Criteria:

          -  Diagnosis of asthma, or other clinically relevant lung disease (other than COPD), e.g.
             sarcoidosis, tuberculosis, pulmonary fibrosis, severe bronchiectasis or lung cancer;
             Subject with alpha-1-antitrypsin deficiency as the underlying cause of COPD

          -  Pulse Oximetry levels <88% (at rest on room air) at screening

          -  Less than 14 days have elapsed from completion of a course of antibiotics or oral
             corticosteroids for a recent COPD exacerbation.

          -  Diagnosis of Pneumonia (chest X-Ray or computed tomography [CT] confirmed) within the
             last 3 months prior to screening

          -  History or current evidence of clinically significant renal disease, diabetes
             mellitus/metabolic syndrome, hypertension or any other clinically significant
             cardiovascular, neurological, endocrine, or hematological abnormalities that are
             uncontrolled on permitted therapy. 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.

          -  A positive pre-study drug/alcohol screen

          -  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 of screening

          -  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 or GSK
             Medical Monitor, contraindicates their participation

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones).

          -  History of regular alcohol consumption within 6 months of the study defined as: For
             non United States of America (US) sites: an average weekly intake of >21 units for
             males or >14 units for females. One unit is equivalent to 8 g of alcohol: a half-pint
             (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of
             spirits; For US sites: an average weekly intake of >14 drinks for males or >7 drinks
             for females. One drink is equivalent to 12 g of alcohol: 12 ounces (360 mL) of beer, 5
             ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits.

          -  Current or expected use of proton pump inhibitors or histamine H2-receptor antagonists
             during the study period

          -  Chest X-ray (posteroanterior with lateral) or CT scan reveals evidence of pneumonia or
             a clinically significant abnormality not believed to be due to the presence of COPD
             (historic data up to 1 yr may be used).

          -  Subjects with peripheral blood neutrophil count (PBN) <2x10^9/Liter

          -  Subject with history of previous lung surgery (e.g. lobectomy, pneumonectomy, or lung
             volume reduction)

          -  Requiring the use of oral or injectable Cytochrome P450 3A4 (CYP3A4) or breast cancer
             resistance protein (BCRP) substrates with a narrow therapeutic index