Batefenterol/Fluticasone Furoate in Treatment of Chronic Obstructive Pulmonary Disease
Batefenterol/Fluticasone Furoate in Treatment of Chronic Obstructive Pulmonary Disease
Batefenterol inhalation powder is currently under development as a fixed-dose combination
 with fluticasone furoate (FF) for the treatment of Chronic Obstructive Pulmonary Disease
 (COPD).

 The present study will administer batefenterol/FF (300/100 micrograms [mcg]) for the first
 time to subjects with COPD, to investigate the safety and tolerability of the combination
 compared with placebo, and to evaluate the pharmacokinetics and pharmacodynamics profiles of
 the individual components when administered in combination.

 This is a Phase IIa, multicenter, randomized, placebo-controlled, double-blind, parallel
 group study. Subjects will be randomized (2:1) to one of the following double-blind treatment
 groups:

 Batefenterol/FF 300/100 mcg inhalation powder once daily, or matching placebo inhalation
 powder once daily.

 Subjects will self-administer the study treatments once daily (QD) in the morning for 42 days
 via a multi-dose dry powder inhaler (DPI) which contains two blister strips. Additionally, an
 inhaled short acting beta2-receptor agonist, albuterol will be provided from screening to the
 end of the treatment period for all subjects to use as needed to relieve COPD symptoms. At
 the end of the treatment period, subjects can resume conventional therapy.

 The study will randomize approximately 60 subjects. The total duration of subject
 participation (from screening to follow-up) will be approximately 8 weeks.
Inclusion Criteria:

 -  Type of subject: Outpatient.

 -  Informed Consent: Capable of giving signed informed consent, which includes compliance
 with pre-specified requirements and restrictions.

 -  Age and gender: Male and female subjects, 40 years of age or older at the time of
 signing the informed consent, are eligible to participate in the study.

 Female subject: is eligible to participate if she is not pregnant (as confirmed by a
 negative urine human chorionic gonadotrophin (hCG) test), not lactating, and at least one
 of the following conditions applies:

 1. Non-reproductive potential defined as:

 Pre-menopausal females with one of the following: documented tubal ligation;
 documented hysteroscopic tubal occlusion procedure with follow-up confirmation of
 bilateral tubal occlusion; hysterectomy; documented bilateral oophorectomy
 Postmenopausal defined as 12 months of spontaneous amenorrhea. Females on hormone
 replacement therapy (HRT) and whose menopausal status is in doubt will be required to
 use one of the highly effective contraception methods if they wish to continue their
 HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of
 post-menopausal status prior to study enrolment.

 2. Reproductive potential and agrees to follow one of the options listed below 30 days
 prior to the first dose of study medication and until at least five terminal
 half-lives OR until any continuing pharmacologic effect has ended, whichever is longer
 after the last dose of study medication and completion of the follow-up visit. This
 list does not apply to females of reproductive potential with same sex partners, when
 this is their preferred and usual lifestyle or for subjects who are and will continue
 to be abstinent from penile-vaginal intercourse on a long term and persistent basis:

 Contraceptive subdermal implant that meets the standard operating procedure (SOP)
 effectiveness criteria including a <1% rate of failure per year, as stated in the product
 label Intrauterine device or intrauterine system that meets the SOP effectiveness criteria
 including a <1% rate of failure per year, as stated in the product label Oral
 Contraceptive, either combined or progestogen alone Injectable progestogen Contraceptive
 vaginal ring Percutaneous contraceptive patches Male partner sterilization with
 documentation of azoospermia prior to the female subject's entry into the study, and this
 male is the sole partner for that subject These allowed methods of contraception are only
 effective when used consistently, correctly and in accordance with the product label. The
 investigator is responsible for ensuring that subjects understand how to properly use these
 methods of contraception.

 -  Chronic Obstructive Pulmonary Disease (COPD): An established clinical history of COPD
 in accordance with the definition by the American Thoracic Society/European
 Respiratory Society.

 -  COPD Disease severity: A post-albuterol forced expiratory volume in 1 second
 (FEV1)/forced vital capacity (FVC) ratio of =<0.70 and a post-albuterol FEV1 >=30 and
 =<80% of predicted normal values calculated using the European Respiratory Society
 Global Lung Function Initiative reference equations at Visit 1.

 -  Smoking history: Current or former cigarette smokers with a history of cigarette
 smoking of >= 10 pack-years at Visit 1. Former smokers are defined as those who have
 stopped smoking for at least 6 months prior to Visit 1.

 Number of pack years = (number of cigarettes per day / 20) x number of years smoked (for
 example, 20 cigarettes per day for 10 years, or 10 cigarettes per day for 20 years both
 equal 10 pack-years).

 Note: Pipe and cigar use cannot be used to calculate pack-year history.

 Exclusion Criteria:

 -  Asthma: A current diagnosis of asthma (Subjects with a prior history of asthma are
 eligible if they have a current diagnosis of COPD).

 -  Other Respiratory Disorders: Known alpha-1 antitrypsin deficiency, active lung
 infections (such as tuberculosis), and lung cancer are absolute exclusionary
 conditions. Other excluded conditions include and not limited to clinically
 significant bronchiectasis, pulmonary hypertension unrelated to COPD, sarcoidosis, or
 interstitial lung disease. Or a subject who, in the opinion of the investigator, has
 any other significant respiratory conditions in addition to COPD

 -  Other Diseases/Abnormalities: Subjects with historical or current evidence of
 clinically significant cardiovascular, neurological, psychiatric, renal, hepatic,
 immunological, endocrine (including uncontrolled diabetes or thyroid disease) or
 hematological abnormalities that are uncontrolled and/or a previous history of cancer
 in remission for <5 years prior to Visit 1 (localized carcinoma of the skin that has
 been resected for cure is not exclusionary). Significant is defined as any disease
 that, in the opinion of the investigator, would put the safety of the subject at risk
 through participation, or which would affect the efficacy or safety analysis if the
 disease/condition exacerbated during the study.

 -  Poorly controlled COPD: defined as the occurrence of 'acute worsening of COPD that is
 managed with corticosteroid and/or antibiotics or that requires treatment prescribed
 by a physician in the 6 weeks prior to Screening (Visit 1)', or 'subjects who are
 hospitalized due to acute worsening of COPD within 12 weeks of Visit 1'.

 -  History of COPD exacerbation: subject who have had more than one exacerbation
 (moderate or severe) within the 12 months prior to Visit 1.

 -  Pneumonia and lower respiratory tract infection: Subjects with lower respiratory tract
 infection that required the use of antibiotics within 6 weeks prior to Visit 1; or
 subjects hospitalized due to pneumonia within 12 weeks of Visit 1.

 -  Use of long-term oxygen therapy (LTOT): Oxygen therapy prescribed for greater than 12
 hours a day. As-needed oxygen use (that is, =<12 hours per day) is not exclusionary.

 -  Nebulized Therapy: Regular use (prescribed for use every day, not for as-needed use)
 of short-acting bronchodilators (for example, albuterol) via nebulized therapy.

 -  Lung Resection: Lung volume reduction surgery within the 12 months prior to Visit 1.

 -  Clinically significant abnormal laboratory finding at Visit 1.

 -  Liver Disease: Current or chronic history of liver disease, or known hepatic or
 biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic
 gallstones).

 -  Presence of hepatitis B surface antigen (HBsAg), or positive hepatitis C antibody test
 result at screening. Subjects with positive Hepatitis C antibody due to prior resolved
 disease can be enrolled, only if a confirmatory negative Hepatitis C ribonucleic acid
 polymerase chain reaction test is obtained.

 -  Abnormal and clinically significant findings from 12-lead electrocardiogram (ECG)
 performed at Visit 1. Site investigators will be provided with ECG over-read conducted
 by a centralized independent cardiologist, to assist in evaluation of subject
 eligibility. For this study, an abnormal and clinically significant ECG 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:

 Sinus bradycardia <45 beats per minute (bpm) (Note: Sinus bradycardia <45 bpm should be
 confirmed by two additional readings at least 5 minutes apart) Sinus tachycardia >=110 bpm
 (Note: Sinus tachycardia >=110 should be confirmed by two additional readings at least 5
 minutes apart) Multifocal atrial tachycardia (wandering atrial pacemaker with rate >100
 bpm) PR interval >240 milliseconds (msec) Evidence of Mobitz II second degree or third
 degree atrioventricular (AV) block Pathological Q waves (defined as wide [>0.04 seconds]
 and deep [>0.4 millivolt (mV) (4 millimeters [mm] with 10 mm/mV setting)] or >25% of the
 height of the corresponding R wave, providing the R wave was >0.5 mV [5 mm with 10 mm/mV
 setting], appearing in at least two contiguous leads (Note: prior evidence [that is, ECG
 obtained at least 12 months prior) of pathological Q waves that are unchanged are not
 exclusionary; and the investigator will determine if the subject is precluded from entering
 the study) Evidence of ventricular ectopic couplets, bigeminy, trigeminy or multifocal
 premature ventricular complexes.

 For subjects without complete right bundle branch block: QT interval corrected by
 Fridericia's method (QTc[F]) >=450 msec or an ECG that is unsuitable for QT measurements
 (for example, poor defined termination of the T wave) For subjects with complete right
 bundle branch block: QTc(F) >=480msec or an ECG that is unsuitable for QT measurements (for
 example, poor defined termination of the T wave) (Note: All potentially exclusionary QT
 measurements should be confirmed by two additional readings at least 5 minutes apart) ST-T
 wave abnormalities (excluding non-specific ST-T wave abnormalities) (Note: prior evidence
 (that is, ECG obtained at least 12 months prior) of ST-T waves that are unchanged are not
 exclusionary and the investigator will determine if the subject is precluded from entering
 the study) Clinically significant conduction abnormalities (for example,
 Wolff-Parkinson-White syndrome or bifascicular block defined as complete left bundle branch
 block or complete right bundle branch block with concomitant left fascicular block)
 Clinically significant arrhythmias (for example, atrial fibrillation with rapid ventricular
 response, ventricular tachycardia)

 -  Medication Prior to Spirometry: Unable to withhold albuterol for the 4 hour period
 required prior to spirometry testing at each study visit.

 -  Excluded Medications: Use of the following medications are not permitted within the
 defined time intervals prior to Visit 1 and throughout the study:

 Depot corticosteroids: 12 weeks Systemic, oral or parenteral corticosteroids: 6 weeks
 Antibiotics (for lower respiratory tract infection): 6 weeks 'Cytochrome P450 3A4' strong
 inhibitors and 'P-glycoprotein' inhibitor: 4 weeks Long acting beta-agonist (LABA)/inhaled
 corticosteroid (ICS) combination products : 4 weeks ICS : 4 weeks Phosphodiesterase 4
 (PDE4) inhibitors (roflumilast): 1 week LABA/ Long-acting muscarinic antagonist (LAMA)
 combination (for example, vilanterol/umeclidinium bromide): 1 week Once-daily beta2-agonist
 (for example, Olodaterol and Indacaterol): 1 week LAMA (tiotropium, aclidinium,
 glycopyrronium, umeclidinium): 1 week Theophylline preparations: 48 hours Oral leukotriene
 inhibitors (zafirlukast, montelukast, zileuton): 48 hours Oral beta2-agonists Long-acting:
 48 hours Short-acting: 12 hours Inhaled LABA (for example, Salmeterol, formoterol): 48
 hours Inhaled sodium cromoglycate or nedocromil sodium: 24 hours Inhaled short acting
 beta2-agonists: 4 hours Inhaled short-acting anticholinergics: 4 hours Inhaled short-acting
 anticholinergic/short-acting beta2-agonist combination products: 4 hours Use of study
 provided albuterol is permitted during the study, except in the 4-hour period prior to
 spirometry testing

 -  Drug or Alcohol Abuse: A known or suspected history of alcohol or drug abuse within 2
 years prior to Visit 1.

 -  Contraindications: Any history of allergy or hypersensitivity to any
 anticholinergic/muscarinic receptor antagonist, beta-2-agonist, sympathomimetic,
 corticosteroid (intranasal, inhaled or systemic) lactose/milk protein, or a medical
 condition such as narrow-angle glaucoma, prostatic hypertrophy or bladder neck
 obstruction, that, in the opinion of the study physician contraindicates study
 participation or use of an inhaled LAMA, LABA or ICS

 -  The subject has participated in a clinical trial and has received an investigational
 product within the following time period 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)

 -  Affiliation with Investigator Site: A subject will not be eligible for this study if
 he/she is an immediate family member of the participating investigator,
 sub-investigator, study coordinator, or employee of the participating investigator.

 -  Inability to read: In the opinion of the investigator, any subject who is unable to
 read and/or would not be able to complete a diary.

 -  Questionable validity of consent: Subjects with a history of psychiatric disease,
 intellectual deficiency, poor motivation or other conditions that will limit the
 validity of informed consent to participate in the study.

 -  Non-compliance: Subjects at risk of non-compliance, or unable to comply with the study
 procedures. Any infirmity, disability, or geographic location that would limit
 compliance for scheduled visits.