A Randomized Study, Comparing Fluticasone Furoate/Umeclidinium/Vilanterol (FF/UMEC/VI) Single Inhaler Triple Therapy, Versus Multiple Inhaler Therapy (Budesonide/Formoterol Plus Tiotropium) in Subjects With Chronic Obstructive Pulmonary Disease (COPD)
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Intervention: budesonide/formoterol; albuterol/salbutamol; FF/UMEC/VI; Placebo to match budesonide/formoterol; tiotropium; Placebo to match FF/UMEC/VI; placebo to match tiotropium; ELLIPTA; MDI; HandiHaler
Intervention description: Subjects will be administered two inhalations of budesonide/formoterol via MDI twice daily; Subjects will be provided short-acting albuterol/salbutamol as-rescue medication to be used on an as-needed basis throughout the study.; Subjects will receive FF/UMEC/VI 100/62.5/25 mcg via ELLIPTA once daily in the morning; Subjects will be administered two inhalations of matching placebo twice daily via MDI; Subjects will receive tiotropium (18 mcg) once daily in the morning via HandiHaler device; Matching placebo to FF/UMEC/VI will be administered via ELLIPTA once daily in the morning.; Subjects will receive tiotropium matching placebo via Handihaler once daily in the morning; Subjects will receive FF/UMEC/VI 100/62.5/25 mcg and matching placebo via ELLIPTA in the treatment period. Budesonide/formoterol plus tiotropium once daily plus placebo will be administered via ELLIPTA during the run-in period.; Subjects will receive budesonide/formoterol and placebo to match budesonide/formoterol via MDI in the treatment period.; Subjects will be administered tiotropium (18 mcg) or placebo to match tiotropium via HandiHaler during the treatment period.
Intervention MeSH terms: Budesonide; Albuterol; Formoterol Fumarate; Tiotropium Bromide; Budesonide, Formoterol Fumarate Drug Combination
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: This is a parallel group study. Eligible subjects will be randomized in a ratio of 1:1 to receive either FF/UMEC/VI single inhaler triple therapy or multiple inhaler triple combination therapy (budesonide/formoterol plus tiotropium) during the treatment period.
Masking: Double (Participant, Investigator)
Masking description: This is a phase 4 double blind study, which will use a triple dummy design for dosing.
Enrollment: 729.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: long-acting muscarinic receptor antagonists; tiotropium; HRQoL; Budesonide/formoterol; chronic obstructive pulmonary disease; COPD

Summary:

      The primary purpose of this study is to evaluate lung function and health related quality of
      life (HRQoL) after 84 days of treatment with a single inhaler triple therapy combination of
      FF/UMEC/VI [100/62.5/25 microgram (mcg)] once daily via the ELLIPTA™ compared with a multiple
      inhaler combination therapy of Symbicort Metered Dose Inhaler (MDI) (budesonide/formoterol
      320/9 mcg) twice daily plus Spiriva HandiHaler (tiotropium 18 mcg) once daily. The study will
      inform healthcare providers that subjects can be effectively and safely switched to
      FF/UMEC/VI single inhaler therapy from a multiple inhaler triple therapy regimen of Symbicort
      MDI and Spiriva Handihaler. Eligible subjects will enter a 4-week run-in period during which
      they will be administered budesonide/formoterol (320/9 mcg) twice daily plus tiotropium (18
      mcg) once daily plus placebo via ELLIPTA. Following the run-in period, subjects will be
      randomized to receive one of the following study treatments for 84 days: 1) FF/UMEC/VI
      100/62.5/25 mcg via ELLIPTA once daily in the morning plus two inhalations of placebo to
      match budesonide/formoterol via MDI, twice daily plus placebo to match tiotropium via
      HandiHaler once daily in the morning or 2) Budesonide/formoterol 320/9 mcg via MDI, twice
      daily plus tiotropium 18 mcg via HandiHaler once daily in the morning plus placebo via
      ELLIPTA once daily in the morning. Subjects will then enter a one week follow-up period. The
      total duration for a subject in the study will be approximately 17 weeks. ELLIPTA is a
      registered trademark of the GlaxoSmithKline group of companies.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subjects must be capable of giving signed informed consent prior to study start.

          -  Only outpatient subjects will be included

          -  Subjects (male or female) must be 40 years of age or older at Screening (Visit 1). A
             female subject 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 until safety follow-up contact after the last dose of study
             treatment

          -  An established clinical history of COPD in accordance with the definition by the
             American Thoracic Society/European Respiratory Society

          -  Current or former cigarette smokers with a history of cigarette smoking of >=10
             pack-years at Screening (Visit 1) [number of pack years = (number of cigarettes per
             day / 20) x number of years smoked (e.g., 20 cigarettes per day for 10 years, or 10
             cigarettes per day for 20 years)]. Previous smokers are defined as those who have
             stopped smoking for at least 6 months prior to Visit 1.

          -  Subjects with a score of >=10 on the COPD Assessment Test (CAT) at Screening (Visit 1)

          -  Subjects must demonstrate a post-bronchodilator FEV1 <50 % predicted normal or a
             post-bronchodilator FEV1 <80 % predicted normal and a documented history of >=2
             moderate exacerbations or one severe (hospitalized) exacerbation in the previous 12
             months. Subjects must also have a measured post albuterol/salbutamol FEV1/forced vital
             capacity (FVC) ratio of <0.70 at screening

          -  Subjects must have been receiving daily maintenance treatment for their COPD for at
             least 3 months prior to Screening

        Exclusion Criteria:

          -  Women who are pregnant or lactating or are planning on becoming pregnant during the
             study

          -  Subjects with a current diagnosis of asthma. (Subjects with a prior history of asthma
             are eligible if they have a current diagnosis of COPD).

          -  Subjects with alpha 1-antitrypsin deficiency as the underlying cause of COPD

          -  Subjects with active tuberculosis, lung cancer, and clinically significant:
             bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung
             disease or other active pulmonary diseases

          -  Subjects who have undergone lung volume reduction surgery within the 12 months prior
             to Screening

          -  Immune suppression (e.g. advanced human immunodeficiency virus [HIV] with high viral
             load and low cluster of differentiation 4 [CD4] count, lupus on immunosuppressants)
             that in the opinion of the investigator would increase risk of pneumonia or other risk
             factors for pneumonia (e.g. neurological disorders affecting control of the upper
             airway, such as Parkinson's Disease, Myasthenia Gravis).

          -  Pneumonia and/or moderate or severe COPD exacerbation that has not resolved at least
             14 days prior to Screening and at least 30 days following the last dose of oral or
             systemic corticosteroids (if applicable)

          -  Respiratory tract infection that has not resolved at least 7 days prior to Screening

          -  Chest x-ray (posteroanterior and lateral) reveals evidence of pneumonia or a
             clinically significant abnormality not believed to be due to the presence of COPD, or
             another condition that would hinder the ability to detect an infiltrate on chest X-ray
             (e.g. significant cardiomegaly, pleural effusion or scarring). All subjects will have
             a chest X-ray at Screening Visit 1 (or historical radiograph or computerized
             tomography [CT] scan obtained within 3 months prior to screening). For sites in
             Germany: If a chest x-ray (or CT scan) within 3 months prior to Screening (Visit 1) is
             not available, approval to conduct a diagnostic chest x-ray will need to be obtained
             from the Federal Office for Radiation Protection (BfS).

          -  Subjects with historical or current evidence of clinically significant cardiovascular,
             neurological, psychiatric, renal, hepatic, immunological, gastrointestinal,
             urogenital, nervous system, musculoskeletal, skin, sensory, endocrine (including
             uncontrolled diabetes or thyroid disease) or hematological abnormalities that are
             uncontrolled. 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.

          -  Unstable liver disease: alanine transaminase (ALT) >2 times Upper Limit of Normal
             (ULN); and bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable
             if bilirubin is fractionated and direct bilirubin <35 %). Current active liver or
             biliary disease (with the exception of Gilbert's syndrome or asymptomatic gallstones
             or otherwise stable chronic liver disease per investigator assessment).

          -  Subjects with any of the following at Screening (Visit 1) would be excluded:
             Myocardial infarction or unstable angina in the last 6 months; Unstable or life
             threatening cardiac arrhythmia requiring intervention in the last 3 months; New York
             Heart Association (NYHA) Class IV Heart failure.

          -  Abnormal and clinically significant 12-lead electrocardiogram (ECG) finding at Visit
             1. 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
             ECG tracing that is interpreted at, but not limited to, any of the following: i)
             Atrial Fibrillation (AF) with rapid ventricular rate >120 beats per minute (BPM); ii)
             Sustained and non-sustained Ventricular tachycardia (VT); iii). Second degree heart
             block Mobitz type II and third degree heart block (unless pacemaker or defibrillator
             had been inserted); iv) QT interval corrected for heart rate by Fridericia's formula
             (QTcF) >=500 milliseconds (msec) in subjects with QRS <120 msec and QTcF >=530 msec in
             subjects with QRS >=120 msec.

          -  A history of allergy or hypersensitivity to any corticosteroid,
             anticholinergic/muscarinic receptor antagonist, beta2-agonist, lactose/milk protein or
             magnesium stearate or a medical condition such as narrow-angle glaucoma, prostatic
             hypertrophy or bladder neck obstruction that, in the opinion of the Investigator,
             contraindicates study participation.

          -  Subjects with carcinoma that has not been in complete remission for at least 3 years.
             Subjects who have had carcinoma in situ of the cervix, squamous cell carcinoma and
             basal cell carcinoma of the skin would not be excluded based on the 3 year waiting
             period if the subject has been considered cured by treatment.

          -  Use of long-term oxygen therapy (LTOT) described as resting oxygen therapy >3 liters
             per minute (L/min) at screening (Oxygen use <=3 L/min flow is not exclusionary)

          -  Subjects who are medically unable to withhold their albuterol/salbutamol for the
             4-hour period required prior to spirometry testing at each study visit

          -  Subjects who have participated in the acute phase of a Pulmonary Rehabilitation
             Programme 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.

          -  Subjects with a known or suspected history of alcohol or drug abuse within the last 2
             years

          -  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

          -  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

          -  Study Investigators, sub-Investigators, coordinators, employees of a participating
             Investigator or study site, or immediate family members of the aforementioned that is
             involved with this study

          -  In the opinion of the Investigator, any subject who is unable to read and/or would not
             be able to complete study related materials

          -  Use of various medication prior to screening.