Comparative Study of Fluticasone Furoate(FF)/Umeclidinium Bromide (UMEC)/ Vilanterol (VI) Closed Therapy Versus FF/VI Plus UMEC Open Therapy 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: FF/UMEC/VI; FF/VI; UMEC; Placebo; Albuterol/salbutamol
Intervention description: This intervention is provided in two strips. First strip contains FF blended with lactose. It is available as dry white powder, 100 mcg per blister. Second strip contains UMEC and VI blended with lactose and magnesium stearate. It is available as dry white powder, 62.5 mcg per blister UMEC, 25 mcg per blister VI. The intervention is inhaled via the DPI, once daily in the morning. DPI contains 30 doses (2 strips with 30 blisters per strip).; This intervention is provided in two strips. First strip contains FF blended with lactose. It is available as dry white powder, 100 mcg per blister. Second strip contains VI blended with lactose and magnesium stearate. It is available as dry white powder, 25 mcg per blister. The intervention is inhaled via the DPI, once daily in the morning. DPI contains 30 doses (2 strips with 30 blisters per strip).; This intervention is available in one strip. The strip contains UMEC blended with lactose and magnesium stearate. The formulation is available as dry white powder, 62.5 mcg per blister. The intervention is inhaled via the DPI, once daily in the morning. DPI contains 30 doses (1 strip with 30 blisters).; This intervention is available in one strip. The strip contains lactose. The formulation is available as dry white powder. The intervention is inhaled via the DPI, once daily in the morning. DPI contains 30 doses (1 strip with 30 blisters).; This is a rescue medication administered via metered-dose inhaler (MDI) with a spacer which will be used when needed during the study.
Intervention MeSH terms: Albuterol
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 1055.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: Chronic Obstructive Pulmonary Disease (COPD); fluticasone furoate/umeclidinium bromide/vilanterol (FF/UMEC/VI); Umeclidinium bromide (UMEC); Closed triple therapy; Placebo; Open triple therapy; fluticasone furoate/vilanterol (FF/VI)

Summary:

      This multicenter study will be conducted to compare the effect of FF/UMEC/VI with FF/VI plus
      UMEC on lung function after 24 weeks of treatment. This is a phase IIIB, 24-week, randomized,
      double-blind, parallel group multicenter study. This study will test the hypothesis that the
      difference in trough forced expiratory volume in one second (FEV1) between treatment groups
      is less than or equal to a pre-specified non-inferiority margin. Alternatively, this study
      will also test the hypothesis that the difference between treatment groups is greater than
      the margin. The triple therapy of FF/UMEC/VI in a single inhaler is being developed with the
      aim of providing a new treatment option for the management of advanced Global Initiative for
      Chronic Obstructive Lung Disease (GOLD) Group D COPD which will reduce the exacerbation
      frequency, allow for a reduced burden of polypharmacy, convenience, and improve lung
      function, health related quality of life (HRQoL) and symptom control over established
      dual/monotherapies. This study has a 2 week run in period where subjects will continue to
      have their existing COPD medications. At randomization, subjects will discontinue all
      existing COPD medications and will be assigned to treatment of FF/UMEC/VI, 100 microgram
      (mcg)/62.5 mcg/25 mcg and placebo or FF/VI, 100 mcg/25 mcg and UMEC, 62.5 mcg in a 1:1 ratio
      for 24 weeks. Subjects will have clinical visits at Pre-Screening (Visit 0), Screening (Visit
      1), Randomization (Week 0, Visit 2), Week 4 (Visit 3), Week 12 (Visit 4) and Week 24 (Visit
      5). A follow-up visit will be conducted at 1 week after the end of treatment period or after
      early withdrawal visit. Approximately, 1020 subjects will be enrolled in this study. There
      will be two pharmacokinetic (PK) groups (subset A and subset B). Approximately 120 subjects
      will be assigned to subset A and approximately 60 subjects will be assigned to subset B. 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.
    

Eligibility criteria:

        Inclusion Criteria:

        Informed Consent: A signed and dated written informed consent prior to study participation.

          -  Type of subject: Outsubject.

          -  Age: Subjects 40 years of age or older at Screening (Visit 1).

          -  Gender: Male or female subjects. A 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:

        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.

        Reproductive potential and agrees to follow one of the options listed in the Modified List
        of Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential
        (FRP) from 30 days prior to the first dose of study treatmentand until after the last dose
        of study treatmentand completion of the follow-up visit.

          -  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 divided by 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 Screening
             (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 (Visit1).

          -  Severity of COPD Disease: A post-albuterol/salbutamol FEV1/FVC ratio of <0.70 at
             Screening (Visit 1).

          -  Existing COPD maintenance treatment: Subject must be receiving daily maintenance
             treatment for their COPD for at least 3 months prior to Screening (Visit 1). Note:
             Subjects receiving only as needed COPD medications are not eligible.

          -  History of Exacerbations: Subjects must demonstrate: a post-bronchodilator FEV1 <50
             percent predicted normal at Screening (Visit 1) and a documented history of >=1
             moderate or severe COPD exacerbation in the 12 months prior to Screening or a
             post-bronchodilator 50 percent =< FEV1 <80 percent predicted normal at Screening
             (Visit 1) and a documented history of >=2 moderate exacerbations or a documented
             history of >=1 severe COPD exacerbation (hospitalised) in the 12 months prior to
             Screening (Visit 1). Notes: Percent predicted will be calculated using the European
             Respiratory Society Global Lung Function Initiative reference equations; 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 hospitalisation (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.

          -  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, which is the primary
             cause of their respiratory symptoms).

          -  Alpha 1-antitrypsin deficiency: Subjects with alpha1-antitrypsin deficiency as the
             underlying cause of COPD.

          -  Other respiratory disorders: Subjects with active tuberculosis are excluded. Subjects
             with other respiratory disorders (e.g. clinically significant: bronchiectasis,
             sarcoidosis, lung fibrosis, pulmonary hypertension, interstitial lung diseases) are
             excluded if these conditions are the primary cause of their respiratory symptoms.

          -  Lung resection: Subjects with lung volume reduction surgery (including procedures such
             as endobronchial valves) within the 12 months prior to Screening (Visit 1).

          -  Risk Factors for Pneumonia: immune suppression (e.g. advanced human immune deficiency
             virus (HIV) with high viral load and low cluster of differentiation 4 (CD4) count,
             Lupus on immunosuppressants that 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). Notes: Subjects at a high
             risk for pneumonia (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 (Visit 1) and at least 30 days following the last dose of
             oral/systemic corticosteroids (if applicable).

          -  Other Respiratory tract infections that have not resolved at least 7 days prior to
             Screening (Visit 1).

          -  Abnormal Chest x-ray: Chest x-ray 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 computerised
             tomography (CT) scan obtained within 3 months prior to Screening (Visit 1). Notes:
             Subjects who have experienced pneumonia and/or moderate or severe COPD exacerbation
             within 3 months of Screening (Visit 1) must provide a post pneumonia/exacerbation
             chest x-ray or have a chest x-ray conducted at Screening (Visit 1); 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).

          -  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: 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 percent). 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). Notes: Stable
             chronic liver disease should generally be defined by the absence of ascites,
             encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or
             persistent jaundice, or cirrhosis; Chronic stable hepatitis B and C (e.g., presence of
             hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test result at
             screening or within 3 months prior to first dose of study treatment) are acceptable if
             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 4 Heart failure.

          -  Abnormal and clinically significant 12-Lead ECG finding: Investigators will be
             provided with ECG reviews conducted by a centralized independent cardiologist to
             assist in evaluation of subject eligibility. 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 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 nonsustained ventricular
             tachycardia (VT); Second degree heart block Mobitz type II and third degree heart
             block (unless pacemaker or defibrillator had been inserted).

          -  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 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.

          -  Oxygen therapy: Use of long-term oxygen therapy (LTOT) described as resting oxygen
             therapy >3 Liters per minute (Oxygen use <= 3 Liters/minute 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.

          -  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, and 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 30 days prior
             to Screening (Visit 1) or requirement for their use during the study: Use of long term
             continuous antibiotic therapy; systemic, oral, parenteral corticosteroids
             (Intra-spinal and intra-articular injections are allowed); use of any other
             investigational drug: within 30 days or 5 half lives whichever is longer.