Danirixin Dose Ranging Study in Participants With Chronic Obstructive Pulmonary Disease (COPD)
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Intervention: Danirixin; Danirixin matching placebo; Standard of care; Rescue medication
Intervention description: Danirixin is available as 5, 10, 25, 35 and 50 mg white, film-coated, oval or round shaped tablets for oral administration.; Danirixin matching placebo will be available as white, film-coated, oval or round shaped tablets for oral administration.; Participants will continue with their standard of care inhaled medications (i.e. long acting bronchodilators with or without inhaled corticosteroids) during the study treatment.; Participants will continue to use rescue medication(s). The following rescue medications may be used: short acting beta agonists, short acting muscarinic antagonists, or short acting combination bronchodilators.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 614.0
Sex: All
Minimum age: 40 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: HCRU exacerbations; SGRQ; CXCR2 antagonist; GSK1325756; Danirixin; COPD

Summary:

      Danirixin (DNX) is a selective CXC chemokine receptor (CXCR2) antagonist being developed as a
      potential anti-inflammatory agent for the treatment of COPD. This is a Phase 2, randomized,
      double-blind (Sponsor Open) study. The primary objective of the study is to evaluate the
      clinical activity and safety of danirixin compared with placebo in participants with COPD.
      Following baseline assessments collected over a 7 day period participants will be randomized
      (1:1:1:1:1:1) to receive one of five dose strengths of danirixin (5 milligram [mg], 10 mg, 25
      mg, 35 mg and 50 mg) or placebo. Study treatment will be administered orally twice daily for
      24 weeks. Participants will continue with their standard of care inhaled medications (i.e.
      long acting bronchodilators with or without inhaled corticosteroids) while receiving study
      treatment. Follow up will continue up to 28 days post last dose. Approximately 700
      participants will be screened with a target of 540 participants completing 24 weeks of
      treatment and key study assessments.
    

Eligibility criteria:

        Inclusion Criteria

          -  Participants must be aged between 40 to 80 years of age inclusive, at the time of
             signing the informed consent.

          -  Participants who have COPD (post bronchodilator FEV1/FVC ratio <0.7 and FEV1%
             predicted >=40%) based on American Thoracic Society (ATS)/European Respiratory Society
             (ERS) current guidelines. Participants with a historical diagnosis of asthma may be
             included so long as they have a current diagnosis of COPD.

          -  History of respiratory symptoms including chronic cough, mucus hypersecretion, and
             dyspnea on most days for at least the previous 3 months prior to screening.

          -  Participants with a documented history of COPD exacerbation(s) in the 12 months prior
             to study participation (screening) meeting at least one of the following criteria: >=2
             COPD exacerbations resulting in prescription for antibiotics and/or oral
             corticosteroids or hospitalization or extended observation in a hospital emergency
             room or outpatient center; 1 COPD exacerbation resulting in prescription for
             antibiotics and/or oral corticosteroids of hospitalization or extended observation in
             a hospital emergency room or outpatient center and a plasma fibrinogen concentration
             at screening >=3 grams/liter (300 milligram/deciliter)

          -  Current and former smokers with a cigarette smoking history of >=10 pack years (1 pack
             year = 20 cigarettes smoked per day for 1 year or equivalent). Current smokers are
             defined as those who are currently smoking cigarettes (i.e. have smoked at least one
             cigarette daily or most days for the month prior to Visit 1). Former smokers are
             defined as those who have stopped smoking for at least 6 months prior to Visit 1.

          -  Participants must have the ability and willingness to use an electronic diary (log
             pad) on a daily basis.

          -  Body weight >=45 kilogram (kg)

          -  Male or female: A male participant must agree to use contraception during the
             treatment period and for at least 60 hours after the last dose of study treatment,
             corresponding to approximately 6 half-lives (which is the time needed to eliminate any
             teratogenic study treatment) and to refrain from donating sperm during this period; A
             female participant is eligible to participate if she is not pregnant, not
             breastfeeding, and at least one of the following conditions applies: Not a woman of
             childbearing potential (WOCBP) OR A WOCBP who agrees to follow the contraceptive
             guidance during the treatment period and for at least 60 hours after the last dose of
             study treatment.

          -  Capable of giving signed informed consent.

        Exclusion Criteria

          -  Diagnosis of other clinically relevant lung diseases (other than COPD), e.g.
             sarcoidosis, tuberculosis, pulmonary fibrosis, severe bronchiectasis or lung cancer.

          -  Alpha-1-antitrypsin deficiency as the underlying cause of COPD

          -  Pulse oximetry <88% at rest at screening. Participants should be tested while
             breathing room air. However, participants living at high altitudes (above 5000 feet or
             1500 meters above sea level) who are receiving supplemental oxygen can be included
             provided they are receiving the equivalent of <4 liter per minute (L/min) and
             screening pulse oximetry is measured while on their usual oxygen settings.

          -  Less than 14 days have elapsed from the completion of a course of antibiotics or oral
             corticosteroids for a recent COPD exacerbation.

          -  A peripheral blood neutrophil count <1.5 x 10^9/L.

          -  Diagnosis of pneumonia (chest X-ray or CT confirmed) within the 3 months prior to
             screening.

          -  Chest x-ray (posterior-anterior with lateral) or CT scan reveals evidence of a
             clinically significant abnormality not believed to be due to the presence of COPD
             (historic results up to 1 year prior to screening may be used). For sites in Germany:
             If a chest x-ray (or CT scan) within 1 year prior to screening is not available,
             approval to conduct a diagnostic chest x-ray will need to be obtained from the Federal
             Office of Radiation Protection (BfS).

          -  History or current evidence of other clinically significant medical condition that is
             uncontrolled on permitted therapies. Significant is defined as any disease that, in
             the opinion of the Investigator, would put the safety of the participant at risk
             through study participation, or that would affect the safety analysis or other
             analysis if the disease/condition worsened during the study.

          -  Current or chronic history of liver disease, or known hepatic or biliary abnormalities
             (with the exception of Gilbert's syndrome or asymptomatic gallstones).

          -  Abnormal and clinically significant 12-lead ECG finding. The investigator will
             determine the clinical significance of each abnormal ECG finding in relation to the
             participant's medical history and exclude participants who would be at undue risk by
             participating in the study. An abnormal and clinically significant finding that would
             preclude a participant from entering the study is defined as a 12-lead tracing that is
             interpreted as, but not limited to, any of the following: atrial fibrillation with
             rapid ventricular rate >120 beats per minute (bpm); sustained or non-sustained
             ventricular tachycardia; second degree heart block Mobitz type II and third degree
             heart block (unless pacemaker or defibrillator has been implanted); Corrected QT
             Interval using Fridericia formula (QTcF) >=500 millisecond (msec) in participants with
             QRS <120 msec and QTcF >=530 msec in participants with QRS >=120 msec.

          -  Previous lung surgery (e.g. lobectomy, pneumonectomy) or lung volume reduction
             procedure.

          -  Current or expected chronic use of macrolide antibiotics during the study period for
             the prevention of COPD exacerbations. Examples of chronic use include, but are not
             limited to, daily or two to three times per week use for at least 3 months.

          -  Oral or injectable CYP3A4 or breast cancer resistance protein (BRCP) substrates with a
             narrow therapeutic index (CYP3A4 substrates include, but are not limited to,
             alfenatil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine,
             sirolimus, tacrolimus, and theophylline; BRCP substrates include, but are not limited
             to, topotecan.) The Investigator should consult with the Medical Monitor if necessary.

          -  Current or expected use of phosphodiesterase-4 inhibitors (e.g. roflumilast).
             Participants currently receiving roflumilast may be included if they are able to
             discontinue use from 30 days prior to screening through the completion of the follow
             up visit.

          -  Participation in a previous clinical trial and has received an investigational product
             within any of the following time periods prior to the first dosing day in the current
             study: 30 days, 5 half lives, or twice the duration of the biological effect of the
             investigational product (whichever is longer).

          -  Participation in a previous clinical trial with danirixin within 1 year prior to the
             first dosing day in the current study

          -  Exposure to more than four investigational products within 1 year prior to the first
             dosing day in the current study.

          -  Alanine transferase (ALT) >2x upper limit of normal (ULN); bilirubin > 1.5xULN
             (isolated bilirubin > 1.5xULN is acceptable if bilirubin is fractionated and direct
             bilirubin <35%).

          -  A positive test for human immunodeficiency virus (HIV) antibody

          -  A positive pre-study hepatitis B surface antigen or positive hepatitis C antibody
             result within 3 months prior to screening.

          -  Pulmonary rehabilitation: Participants who have taken part in the acute phase of a
             pulmonary rehabilitation program within 4 weeks prior to screening or participants who
             plan to enter the acute phase of a pulmonary rehabilitation program during the study.
             Participants who are in the maintenance phase of a pulmonary rehabilitation program
             are not excluded.

          -  A history of allergy or hypersensitivity to any of the ingredients in the study
             treatment.

          -  A known or suspected history of alcohol or drug abuse within the 2 years prior to
             screening.

          -  Inability to read: in the opinion of the Investigator, any participant who is unable
             to read and/or would not be able to complete study related materials.

          -  Affiliation with the study site: study investigators, sub-investigators, study
             coordinators, employees of a study investigator, sub-investigator or study site, or
             immediate family member of any of the above that are involved with the study.