A Study Comparing the Efficacy, Safety and Tolerability of Fixed Dose Combination (FDC) of FF/UMEC/VI With the FDC of FF/VI and UMEC/VI; Administered Once-daily Via a Dry Powder Inhaler (DPI) 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: fluticasone furoate (FF); vilanterol (VI); umeclidinium bromide (UMEC)
Intervention description: FF will be available in combination as dry powder for inhalation as FF/UMEC/VI 100 mcg/62.5 mcg/25 mcg and FF/VI 100 mcg/25 mcg; VI will be available in combination as dry powder for inhalation as FF/UMEC/VI 100 mcg/62.5 mcg/25 mcg, FF/VI 100 mcg/25 mcg and UMEC/VI 62.5 mcg/25 mcg; UMEC will be available in combination as dry powder for inhalation as FF/UMEC/VI 100 mcg/62.5 mcg/25 mcg, and UMEC/VI 62.5 mcg/25 mcg
Intervention MeSH terms: Fluticasone; Xhance; Bromides
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 10355.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: COPD; umeclidinium; fluticasone furoate; vilanterol; triple therapy; exacerbation

Summary:

      The study evaluates the efficacy of fluticasone furoate/umeclidinium bromide/vilanterol
      (FF/UMEC/VI) to reduce the annual rate of moderate and severe exacerbations compared with
      dual therapy of FF/VI or UMEC/VI in subjects with COPD. Published studies which assessed the
      use of an 'open' triple therapy (use of Inhaled Corticosteroid [ICS]/ Long-acting Muscarinic
      Receptor Antagonists [LAMA])/ Long Acting Beta-Agonist [LABA] delivered via multiple
      inhalers) in moderate-severe COPD patients, reported improvements in lung function, Health
      Related Quality of Life (HRQoL), hospitalization rates and rescue medication use, compared to
      dual therapy (ICS/LABA) or LAMA alone. These studies have also shown similar safety profile
      with dual or monotherapy doses for periods of up to one year. Given the clinical experience
      with FF, UMEC and VI, and that the associated risks with these compounds are anticipated from
      their known pharmacology, the potential benefit of a new therapy option in patients with
      moderate to severe COPD supports the further development of the closed triple combination
      (delivered via one inhaler). In the current study subjects meeting all inclusion/exclusion
      criteria will complete 2-week run-in period; 52 week treatment period and a 1-week safety
      follow-up period. Eligible subjects will be randomized to one of the following double-blind
      treatment groups FF/UMEC/VI 100 micrograms (mcg)/62.5 mcg/25 mcg once daily (QD), FF/VI 100
      mcg/25 mcg QD, or UMEC/VI 62.5 mcg/25 mcg QD
    

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 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

          -  Severity of COPD Disease: A post-albuterol/salbutamol FEV1/ Forced Vital Capacity
             (FVC) ratio of <0.70 at Screening

          -  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 Pro re nata (PRN) COPD medications are not eligible

          -  History of Exacerbations: Subjects must demonstrate: a post-bronchodilator FEV1 <50%
             predicted normal and a documented history of >= 1 moderate or severe COPD exacerbation
             in the previous 12 months OR a post-bronchodilator 50% <=FEV1 < 80% predicted normal
             and a documented history of >= 2 moderate exacerbations or a documented history of >=1
             severe COPD exacerbation (hospitalized) in the previous 12 months. 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 dyspnea,
             sputum volume, or sputum purulence (color). Subject verbal reports are not acceptable

          -  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%)

          -  French subjects: In France, a subject will be eligible for inclusion in this study
             only if either affiliated to or a beneficiary of a social security category

        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). Patients at potentially high risk (e.g. very low 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

          -  Other Respiratory tract infections that have 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 chest x-ray at Screening Visit 1 (or historical radiograph or
             computerised 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 chest x-ray to be over-read by the central vendor or
             have a chest x-ray 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 chest x-ray will need to be obtained from the Federal Office for
             Radiation Protection (Bundesamt für Strahlenschutz [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
             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 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 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); sustained or nonsustained
             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 (QTcF) >=500 milliseconds (msec) in patients with QRS <120
             msec and QTcF >=530 msec in patients 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 >3 Liter/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: Use of the following medications within the following
             time intervals prior to Screening (Visit 1) 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 during the study); 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)