A Comparison Study Between the Fixed Dose Triple Combination of Fluticasone Furoate/ Umeclidinium/ Vilanterol Trifenatate (FF/UMEC/VI) With Budesonide/Formoterol 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: Triple FF/UMEC/VI; Placebo to match FF/UMEC/VI; Budesonide/Formoterol; Placebo to match Budesonide/Formoterol combination; Albuterol/salbutamol
Intervention description: The combination will be provided as inhalation via an ELLIPTA DPI having 30 doses (2 strips with 30 blisters per strip). It will have 100 mcg of FF (blended with lactose) per blister, 62.5 mcg of UMEC (blended with lactose and magnesium stearate) per blister and 25 mcg of VI (blended with lactose) per blister.; The placebo (Lactose) will be provided as inhalation via an ELLIPTA DPI having 30 doses (2 strips with 30 blisters per strip).; The combination (400 mcg Budesonide/12 mcg Formoterol) will be provided as inhalation via TURBOHALER with 60 doses.; The placebo (Lactose) will be provided as inhalation via TURBOHALER with 60 doses.; Albuterol/salbutamol will be available as an inhalation via metered-dose inhaler (MDI) with a spacer and will be issued for reversibility testing at Visit 1 Albuterol/salbutamol MDI or NEBULES™ for as needed (prn) use throughout the study will be provided starting at Visit 1.
Intervention MeSH terms: Budesonide; Albuterol; Formoterol Fumarate; Budesonide, Formoterol Fumarate Drug Combination
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 1811.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: Triple Therapy; Formoterol; Respiratory; COPD; Budesonide; Vilanterol; Fluticasone Furoate; Umeclidinium; Lung Function

Summary:

      This is a phase IIIa, randomised, double-blind, double-dummy, parallel group multicenter
      study evaluating once daily FF/UMEC/VI (100 microgram [mcg]/62.5 mcg/25 mcg) inhalation
      powder versus twice daily budesonide/formoterol (400 mcg/12 mcg). The primary purpose of this
      study is to demonstrate improvements in lung function and health status for subjects treated
      with FF/UMEC/VI compared with budesonide/formoterol for 24 weeks. Once-daily 'closed' triple
      therapy of a Inhaled Corticosteroid/ Long-acting Muscarinic Receptor Antagonists/ Long Acting
      Beta-Agonist (ICS/LAMA/LABA) combination FF/UMEC/VI (100 mcg/62.5 mcg/25 mcg) in a single
      device is being developed with the aim of providing a new treatment option for the management
      of advanced (GOLD Group D) COPD which will reduce the exacerbation frequency, allow for a
      reduced burden of polypharmacy, convenience, and increase the potential for improvement in
      lung function, Health Related Quality of Life (HRQoL) and symptom control over established
      dual/monotherapies.

      Subjects meeting all inclusion/exclusion criteria and who have successfully completed all
      protocol procedures at the Screening Visit will enter the two-week run-in period. Following
      the run-in period, eligible subjects will be randomised (1:1) to one of the following
      double-blind treatment groups: FF/UMEC/VI 100 mcg/62.5 mcg/25 mcg via the ELLIPTA™ dry powder
      inhaler (DPI) once daily in the morning and placebo via reservoir inhaler twice daily OR
      Budesonide/formoterol 400 mcg/12 mcg via reservoir inhaler twice daily and placebo via the
      ELLIPTA DPI once daily in the morning.

      The target enrollment is 1800 randomised subjects at approximately 200 study centers
      globally. The total duration of subject participation will be approximately 27 weeks,
      consisting of a 2-week run-in period, 24-week treatment period and a 1-week follow-up period.
      Subjects will run-in on their existing COPD medications for 2 weeks and in addition will be
      provided with short acting albuterol/salbutamol to be used on an as-needed basis (rescue
      medication) throughout the study. Subjects will discontinue all existing COPD medications
      during the randomised treatment period but may continue their study supplied rescue
      albuterol/salbutamol. A sub-set of approximately 400 subjects will remain on blinded study
      treatment for up to a total of 52 weeks to provide additional long term safety data.

      ELLIPTA and NUBULES are a trade marks of the GlaxoSmithKline Group of Companies. Other
      company or product names mentioned herein may be the property of their respective owners
    

Eligibility criteria:

        Inclusion Criteria:

          -  Informed Consent: A signed and dated written informed consent prior to study
             participation.

          -  Type of subject: Outpatient.

          -  Age: Subjects 40 years of age or older at Screening (Visit 1).

          -  Gender: Male or female subjects. A female is eligible to enter and participate in the
             study if she is of: Non-child bearing potential (i.e. physiologically incapable of
             becoming pregnant, including any female who is post-menopausal or surgically sterile).
             Surgically sterile females are defined as those with a documented hysterectomy and/or
             bilateral oophorectomy or tubal ligation. Post-menopausal females are defined as being
             amenorrhoeic for greater than 1 year with an appropriate clinical profile, e.g. age
             appropriate, >45 years, in the absence of hormone replacement therapy. OR Child
             bearing potential, has a negative pregnancy test at screening, and agrees to one of
             the following acceptable contraceptive methods used consistently and correctly (i.e.
             in accordance with the approved product label and the instructions of the physician
             for the duration of the study - screening to safety follow-up contact): Abstinence,
             Oral Contraceptive, either combined or progestogen alone, Injectable progestogen,
             Implants of levonorgestrel, Estrogenic vaginal ring, Percutaneous contraceptive
             patches, Intrauterine device (IUD) or intrauterine system (IUS), Male partner
             sterilization (vasectomy with documentation of azoospermia) prior to the female
             subject's entry into the study, and this male is the sole partner for that subject.
             For this definition, "documented" refers to the outcome of the
             investigator's/designee's medical examination of the subject or 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.; Double barrier method: condom
             and an occlusive cap (diaphragm or cervical/vault caps) with a vaginal spermicidal
             agent (foam/gel/film/cream/suppository)

          -  COPD Diagnosis: An established clinical history of COPD in accordance with the
             definition by the American Thoracic Society/European Respiratory Society.

          -  Smoking History: 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. Note: Pipe and/or
             cigar use cannot be used to calculate pack-year history.

          -  Severity of COPD symptoms: A score of >=10 on the COPD Assessment Test (CAT) at
             Screening (Visit 1).

          -  Severity of Disease: Subjects must demonstrate at Screening: <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/FVC ratio of <0.70 at screening. Note: Percent predicted
             will be calculated using the European Respiratory Society Global Lung Function
             Initiative reference equations. Note: A documented history of a COPD exacerbation
             (e.g., medical record verification) is a medical record of worsening COPD symptoms
             that required systemic/oral corticosteroids and/or antibiotics (for a moderate
             exacerbation) or hospitalization (for a severe exacerbation). Prior use of antibiotics
             alone does not qualify as an exacerbation history unless the use was associated with
             treatment of worsening symptoms of COPD, such as increased dyspnoea, sputum volume, or
             sputum purulence (colour). Subject verbal reports are not acceptable.

          -  Existing COPD maintenance treatment: Subject must be receiving daily maintenance
             treatment for their COPD for at least 3 months prior to Screening. Note: Subjects
             receiving only as required (PRN) COPD medications are not eligible.

          -  Liver function tests: alanine aminotransferase (ALT) <2x upper limit of normal (ULN);
             alkaline phosphatase <=1.5xULN; bilirubin <=1.5xULN (isolated bilirubin >1.5 x ULN is
             acceptable if bilirubin is fractionated and direct bilirubin <35%).

        Exclusion Criteria:

          -  Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant
             during the study.

          -  Asthma: Subjects with a current diagnosis of asthma. (Subjects with a prior history of
             asthma are eligible if they have a current diagnosis of COPD). Alpha1-antitrypsin
             deficiency: Subjects with alpha1-antitrypsin deficiency as the underlying cause of
             COPD.

          -  Other respiratory disorders: Subjects with active tuberculosis, lung cancer,
             significant bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension,
             interstitial lung diseases or other active pulmonary diseases.

          -  Lung resection: Subjects with lung volume reduction surgery within the 12 months prior
             to Screening.

          -  Risk Factors for Pneumonia: immune suppression (e.g. Human immunodeficiency virus
             [HIV], Lupus) or other risk factors for pneumonia (e.g. neurological disorders
             affecting control of the upper airway, such as Parkinson's Disease, Myasthenia
             Gravis). Subjects at potentially high risk (e.g. very low Body mass index [BMI],
             severely malnourished, or very low FEV1) will only be included at the discretion of
             the investigator.

          -  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/systemic corticosteroids (if applicable). In addition, any subject that
             experiences pneumonia and/or moderate or severe COPD exacerbation during the run-in
             period will be excluded.

          -  Respiratory tract infection that has not resolved at least 7 days prior to Screening.

          -  Abnormal Chest X-ray (CXR): 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 CXR (e.g. significant cardiomegaly, pleural effusion or scarring). All
             subjects will have a CXR at Screening Visit 1) (or historical radiograph or Computed
             Tomography [CT] scan obtained within 3 months prior to screening) that will be
             over-read by a central vendor. Note: Subjects who have experienced pneumonia and/or
             moderate or severe COPD exacerbation within 3 months of screening must provide a post
             pneumonia/exacerbation CXR to be over-read by the central vendor or have a CXR
             conducted at 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
             CXR will need to be obtained from the Federal Office for Radiation Protection (BfS).

          -  Other diseases/abnormalities: 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
             haematological 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. For subjects taking part in the
             physical activity monitor subset: Orthopaedic, neurological or other complaints that
             significantly impair normal biomechanical movement patterns and limit the ability to
             walk/cycle, as judged by the Investigator.

          -  Unstable liver disease as defined by the presence of ascites, encephalopathy,
             coagulopathy, hypoalbuminaemia, esophageal or gastric varices or persistent jaundice,
             cirrhosis, known biliary abnormalities (with the exception of Gilbert's syndrome or
             asymptomatic gallstones). Note: Chronic stable hepatitis B and C are acceptable if the
             subject otherwise meets entry criteria.

          -  Unstable or life threatening cardiac disease: 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:
             Investigators will be provided with ECG reviews conducted by a centralized independent
             cardiologist to assist in evaluation of subject eligibility. The Principal
             Investigator (PI) 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 heart block Mobitz type
             II and third degree heart block (unless pacemaker or defibrillator had been inserted);
             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.

          -  Contraindications: 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.

          -  Cancer: Subjects with carcinoma that has not been in complete remission for at least 5
             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 5 year waiting
             period if the subject has been considered cured by treatment.

          -  Oxygen therapy: Use of long-term oxygen therapy (LTOT) described as resting oxygen
             therapy >3litres/minute (L/min) (Oxygen use <=3L/min flow is not exclusionary.)

          -  Medication prior to spirometry: Subjects who are medically unable to withhold their
             albuterol/salbutamol for the 4-hour period required prior to spirometry testing at
             each study visit.

          -  Pulmonary rehabilitation: Subjects who have participated 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.

          -  Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug
             abuse within the last 2 years.

          -  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.

          -  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.

          -  Affiliation with investigator site: study investigators, sub-investigators, study
             coordinators, employees of a participating investigator or study site, or immediate
             family members of the aforementioned that is involved with this study.

          -  Inability to read: In the opinion of the investigator, any subject who is unable to
             read and/or would not be able to complete study related materials.

          -  Medication prior to screening: No use of the following medications within the
             following time intervals prior to Screening or during the study. Long term antibiotic
             therapy: Subjects receiving antibiotics for long term therapy are not eligible for the
             study (Antibiotics are allowed for the short term treatment of an exacerbation or for
             short term treatment of other acute infections); Systemic, Oral, parenteral
             corticosteroids: 30 days (Except during the study oral/systemic corticosteroids may be
             used to treat COPD exacerbations/pneumonia). Intra-articular injections are allowed.
             Any other investigational drug: 30 days or 5 half lives whichever is longer.