Study to Compare the Addition of Umeclidinium Bromide (UMEC) to Fluticasone Furoate (FF)/Vilanterol (VI), With Placebo Plus FF/VI in Subjects With Chronic Obstructive Pulmonary Disease (COPD) -Study 2
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Intervention: FF; VI; UMEC; Placebo
Intervention description: Dry white powder containing 100mcg of Fluticasone Furoate blended with lactose per blister was administered by DPI.; Dry white powder containing 25mcg of Vilanterol micronised drug (as the 'M' salt triphenylacetate) blended with lactose and magnesium stearate per blister was administered by DPI.; Umeclidinium bromide in a powder blend with lactose and magnesium stearate was used at two different doses 62.5mcg and 125mcg.; The matching placebo DPI identical in appearance to the inhaler containing active study medication.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 620.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: long acting beta2- receptor agonist; long acting muscarininc receptor antagonist; dry powder inhaler; safety; COPD; inhaled corticosteroid; efficacy; fluticasone furoate/vilanterol; umeclidinium bromide

Summary:

      After screening, subjects will enter a 4 week open-label run-in period with fluticasone
      furoate (FF)/vilanterol (VI) 100/25 mcg administered once daily via dry powder inhaler (DPI).
      Subjects will then be randomized to receive any one of the 3 treatments (umeclidinium bromide
      [UMEC] [62.5 mcg] administered once daily via a DPI; OR UMEC [125 mcg] administered once
      daily via a DPI; OR matching placebo administered once daily via a DPI), while continuing
      treatment with open label FF/VI 100/25 mcg during a 12-week treatment period. There will be a
      total of eight scheduled clinic visits at Pre-Screening (Visit0), Screening (Visit 1),
      blinded treatment Day 1(Visit2), 2(Visit3), 28 (Visit4), 56 (Visit5), 84 (Visit6) and 85
      (Visit7). A follow-up phone contact will be conducted approximately 7 days after the last
      clinic visit. The total duration of subject participation in the study from Screening to
      Follow-up will be approximately 17 weeks.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Type of subject: Outpatient.

          -  Informed Consent: A signed and dated written informed consent prior to study
             participation.

          -  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 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) that meets the SOP
             effectiveness criteria as stated in the product label

          -  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)

          -  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 [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)]. Former smokers are defined as those who have stopped smoking
             for at least 6 months prior to Visit 1. Pipe and/or cigar use cannot be used to
             calculate pack year history.

          -  Severity of Disease: A pre and post-albuterol/salbutamol FEV1/FVC ratio of <0.70 and a
             pre and post-albuterol/salbutamol FEV1 of <=70% of predicted normal values at Visit 1
             (Screening) calculated using Nutrition Health and Examination Survey (NHANES) III
             reference equations.

          -  Dyspnea: A score of >=2 on the mMRC Dyspnea Scale at Visit 1.

          -  QTc Criteria:

          -  QTc(F) <450 milliseconds (msec) or

          -  QTc(F) <480msec for patients with QRS duration >=120msec

          -  The QTc is the QT interval corrected for heart rate according to either Bazett's
             formula (QTcB), Fridericia's formula (QTcF), or another method, machine or manual
             overread.

          -  For subject eligibility and withdrawal, QTcF will be used.

          -  For purposes of data analysis, QTcF will be used as primary.

          -  The QTc should be based on single or averaged QTc values of triplicate
             electrocardiograms (ECGs) obtained over a brief recording period.

        Exclusion Criteria:

          -  Pregnancy: Women who are pregnant or lactating or are planning on becoming pregnant
             during the study.

          -  Asthma: A current diagnosis of asthma.

          -  Other Respiratory Disorders: Known alpha-1 antitrypsin deficiency, active lung
             infections (such as tuberculosis), and lung cancer are absolute exclusionary
             conditions. A subject who, in the opinion of the investigator, has any other
             significant respiratory conditions in addition to COPD should be excluded. Examples
             may include clinically significant bronchiectasis, pulmonary hypertension,
             sarcoidosis, or interstitial lung disease.

          -  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.

          -  Contraindications: Any history of allergy or hypersensitivity to any
             anticholinergic/muscarinic receptor antagonist, beta2-agonist, sympathomimetic,
             corticosteroid (intranasal, inhaled or systemic) 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 study physician
             contraindicates study participation or use of an inhaled Long acting muscarinic
             antagonist (LAMA), Long acting beta agonist (LABA) or Inhaled corticosteroids (ICS).

          -  Hospitalization: Hospitalization for COPD or pneumonia within 12 weeks prior to Visit
             1.

          -  Lower respiratory tract infection: Subjects with lower respiratory tract infection
             that required the use of antibiotics within 6 weeks prior to Visit 1.

          -  Lung Resection: Subjects with lung volume reduction surgery within the 12 months prior
             to Visit 1.

          -  12-Lead ECG: An abnormal and clinical significant ECG finding from the 12-lead ECG
             conducted at Visit 1. Investigators will be provided with ECG reviews conducted by a
             centralized independent cardiologist to assist in evaluation of subject eligibility.
             The study investigator will determine the medical significance of any ECG
             abnormalities.

          -  Clinically significant and abnormal laboratory finding at Screening (Visit1). After
             discussion with the Medical Monitor, the investigator may have the option to verify
             the abnormal lab result prior to Visit2

          -  Medication Prior to Spirometry: Unable to withhold albuterol/salbutamol 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 1and throughout the study:

          -  No use within 12 weeks prior to Screening Visit 1 or thereafter at any time during the
             study: Depot corticosteroids.

          -  No use within 6 weeks prior to Screening Visit 1 or thereafter at any time during the
             study: Systemic, oral or parenteral corticosteroids (Intra-articular corticosteroid
             injections are permitted.), Antibiotics (for lower respiratory tract infection),
             Cytochrome P450 3A4 strong inhibitors.

          -  No use within 14 days prior to Screening Visit 1 or thereafter at any time during the
             study: Phosphodiesterase 4 inhibitors (roflumilast).

          -  No use within 10 days prior to Screening Visit 1 or thereafter at any time during the
             study: Olodaterol and Indacaterol.

          -  No use within 7 days prior to Screening Visit 1 or thereafter at any time during the
             study: Long acting muscarinici antagonists (tiotropium, aclidinium, glycopyrronium).

          -  No use within 48 hrs prior to Screening Visit 1 or thereafter at any time during the
             study: Theophyllines, Oral leukotriene inhibitors (zafirlukast, montelukast,
             zileuton), Salmeterol and formoterol, ICS/LABA combinations (e.g., fluticasone
             propionate/salmeterol, mometasone furoate/formoterol fumarate, budesonide/formoterol
             fumarate), Oral beta2-agonists Long-acting.

          -  No use within 24 hrs prior to Screening Visit 1 or thereafter at any time during the
             study: Inhaled sodium cromoglycate or nedocromil sodium.

          -  No use within 12 hrs prior to Screening Visit 1 or thereafter at any time during the
             study: Oral beta2-agonists Short-acting.

          -  No use within 4 hrs prior to Screening Visit 1 or thereafter at any time during the
             study: Inhaled short acting beta2-agonists (use of study provided prn
             albuterol/salbutamol is permitted during the study, except in the 4-hour period prior
             to spirometry testing.), Inhaled short-acting anticholinergics, Inhaled short-acting
             anticholinergic/short-acting beta2-agonist combination products.

          -  No use within 30 days or 5 half lives whichever is longer prior to Screening Visit 1
             or thereafter at any time during the study: Any other investigational drug.

          -  Prior enrolment in one of the replicate studies: subjects who have previously been
             assigned a subject number (enrolled) in study 200110 that is a replicate study of
             200109.

          -  Oxygen: Use of long-term oxygen therapy (LTOT) described as oxygen therapy prescribed
             for greater than 12 hours a day. As-needed oxygen use (i.e., <=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 (e.g., albuterol/salbutamol) via nebulized therapy.

          -  Pulmonary Rehabilitation Program: Participation in the acute phase of a pulmonary
             rehabilitation program within 4 weeks prior to Visit 1, or who will 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 or Alcohol Abuse: A known or suspected history of alcohol or drug abuse within 2
             years prior to Visit 1.

          -  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 questionnaire.