RELOVAIR® Lung Deflation Study
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Lung Diseases; Pulmonary Disease, Chronic Obstructive
Intervention: Fluticasone Furoate; Vilanterol
Intervention description: 100mcg Once daily; 25mcg Once daily
Intervention MeSH terms: Fluticasone; Xhance
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 45.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No

Summary:

      The primary objective of the study is to test the hypothesis that lung hyperinflation
      contributes to cardiac dysfunction in COPD and that the treatment of lung deflation with
      FF/VI Inhalation Powder 100/25 mcg administered once daily (QD) will result in the reversal
      of this cardiac dysfunction compared with placebo. This will be assessed by measures of right
      and left global and regional systolic and diastolic cardiac function as assessed using a 30
      minute CMR.

      A secondary objective will be to investigate the effect of FF/VI inhalation powder 100/25mcg
      QD on measures of arterial stiffness in the form of pulse wave analysis and distensability in
      the pulmonary and systemic circulation.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Type of subject: Outpatient.

          -  Informed consent: Subjects must give their signed and dated written informed consent
             to participate.

          -  Gender: Males or females. Female subjects must be post-menopausal or using a highly
             effective method for avoidance of pregnancy. The decision to include or exclude women
             of childbearing potential may be made at the discretion of the investigator in
             accordance with local practice in relation to adequate contraception.

          -  Age 40 and above

          -  Smoking history of at least 15 pack years. Previous smokers are defined as those who
             have stopped smoking for at least 6 months prior to Visit 1.

          -  Established diagnosis of COPD according to ATS/ERS criteria: Subjects with a measured
             post-albuterol/salbutamol FEV1 less than 70% of predicted normal values; FEV1/FVC
             ratio after bronchodilator less than 0.7; Post-bronchodilator spirometry will be
             performed approximately 15 minutes after the subject has self-administered 4
             inhalations (i.e., total 400mcg) of salbutamol via an MDI with a valved-holding
             chamber. The FEV1/FVC ratio and FEV1 percent predicted values will be calculated; MRC
             SCORE greater than 1

          -  Residual Volume (RVol) greater than and equal to 20% above predicted value
             demonstrating evidence of reversibility post bronchodilator of greater than and equal
             to 7.5% predicted.

        Exclusion Criteria:

          -  Pregnancy: Women who are pregnant or lactating.

          -  Asthma: Subjects with a current diagnosis of asthma. (Subjects with a prior history of
             asthma are eligible if they also have a current diagnosis of COPD).

          -  α1-antitrypsin deficiency: Subjects with known α-1 antitrypsin deficiency as the
             underlying cause of COPD

          -  Other respiratory disorders: Subjects with active tuberculosis or lung cancer as well
             as clinically significant bronchiectasis, sarcoidosis, pulmonary fibrosis,
             interstitial lung diseases or other active pulmonary diseases. Pulmonary hypertension
             from causes other than COPD.

          -  Lung resection or transplantation: Subjects with lung volume reduction surgery within
             the 12 months prior to Screening or having had a lung transplant or pneumonectomy.

          -  A moderate/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 corticosteroids (if
             applicable).

          -  Lower respiratory tract infection: Subjects with lower respiratory tract infection
             that required the use of antibiotics within 6 weeks prior to screening.

          -  Pulmonary Rehabilitation: Patients to be excluded if they have been in the acute phase
             of pulmonary rehabilitation in the 4 weeks prior to screening

          -  Current severe heart failure (New York Heart Association class IV) [New York
             HeartAssociation, 1994]. Subjects will also be excluded if they have a known ejection
             fraction of less than 30%.

          -  Abnormal and clinically significant 12-lead ECG

          -  Other systemic inflammatory conditions associated with chronic inflammation in the
             opinion of the investigator (e.g. rheumatoid arthritis, connective tissue disorders
             and Inflammatory Bowel Disease)

          -  Other significant diseases / abnormalities: Any life-threatening condition with life
             expectancy greater than 1 year, other than vascular disease or COPD, that might
             prevent the subject from completing the study.

          -  Coronary Artery Bypass Grafting (CABG) in the 6 months prior to screening.

          -  Myocardial infarction, cerebrovascular event or coronary artery intervention other
             than CABG in the 1 month prior to screening.

        Inclusion of these patients with events over 1 month prior to screening will be based on
        physician's judgment.

          -  History of malignancy within the past 5 years, other than non-melanoma skin cancer.

          -  End stage chronic renal disease: Subjects will be excluded if on renal replacement
             therapy (hemodialysis or peritoneal). Drug/food allergy: Subjects with a history of
             hypersensitivity to any of the study medications (e.g. beta-agonists, corticosteroid)
             or components of the inhalation powder (e.g. lactose, magnesium stearate). In
             addition, patients with a history of severe milk protein allergy that, in the opinion
             of the study physician, contraindicates the subject's participation will also be
             excluded.

          -  Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug
             abuse within the last 2 years.

          -  Oxygen therapy: Subjects receiving treatment with long-term oxygen therapy (LTOT) or
             nocturnal oxygen therapy required for greater than 12 hours a day. Oxygen should not
             be initiated during the trial.

          -  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 or the potential compliance
             to study procedures.

          -  Additional medication: Use of an investigational device or investigational drug within
             30 days or 5 half-lives (whichever is longer) preceding the first dose of study
             medication.

          -  Use of the following medications is not permitted within the following timeframes:
             Prohibited Treatment: Depot corticosteroids, Time: 12 weeks; Prohibited Treatment:
             Cytochrome P450 3A4 strong inhibitors including but not limited to antiretrovirals
             (protease inhibitors) (e.g., indinavir, nelfinavir, ritonavir, saquinavir,
             atazanavir); imidazole and triazole anti- fungals (e.g., ketaconazole, itraconazole,
             voriconazole); clarithromycin, telithromycin, troleandomycin, mibefradil, cyclosporin,
             nefazodone, Time: 6 weeks, Grapefruit is allowed up to Visit 1, then limited to no
             more than one glass of grapefruit juice (250 mL/8 ounces) or one grapefruit per day
             (The use of cytochrome p450 3A4 inhibitors and inducers in the presence of significant
             liver impairment will result in the participant being excluded from the trial);
             Prohibited Treatment: Systemic, oral, parenteral (intra-articular) corticosteroids,
             Time: 30 days; Prohibited Treatment: Antibiotics, Time: 6 weeks; Prohibited Treatment:
             Inhaled corticosteroids, Time: 2 weeks; Inhaled ICS/LABA combination products, Time: 2
             weeks; Prohibited Treatment: Long-acting anticholinergics (e.g., tiotropium), Time: 4
             days; Prohibited Treatment: PDE-4 inhibitors (e.g., roflumilast), Time: 1 week;
             Prohibited Treatment: Oral leukotriene inhibitors (e.g., zafirlukast, montelukast,
             zileuton), Time: 48 hours; Prohibited Treatment: Inhaled long acting beta2-agonists
             (LABA) (e.g., salmeterol), Time: 48 hours; Prohibited Treatment: Oral beta-agonists,
             Time: 48 hours; Prohibited Treatment: Inhaled sodium cromoglycate or nedocromil
             sodium, Time: 24 hours; Prohibited Treatment Ipratropium/albuterol (salbutamol)
             combination product, Time: 6 hours; Prohibited Treatment: Short-acting
             anti-cholinergics (e.g., ipratropium bromide), Time: 6 hours (ipratropium will be
             supplied for rescue during the study, in inhaled or nebulized form); Prohibited
             Treatment: Theophylline preparations, Time: 48 hours; Prohibited Treatment: Inhaled
             short-acting beta2-agonists, Time: 6 hours (albuterol/salbutamol will be supplied for
             rescue during the study, in inhaled or nebulized form)