Fluticasone Propionate/Salmeterol Combination 250/50 DISKUS in the Exercise Endurance Time in Patients With Chronic Obstructive Pulmonary Disease
Condition: Pulmonary Disease, Chronic Obstructive
MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
Intervention: fluticasone propionate/salmeterol inhalation powder DISKUS 250/50; tiotropium bromide inhalation powder HandiHaler
Intervention description: Experimental comparator consisting of inhaled corticosteroid plus long-acting beta agonist combination also known as ADVAIR DISKUS; Open-label drug also known as Spiriva HandiHaler
Intervention MeSH terms: Fluticasone; Xhance; Bromides; Tiotropium Bromide; Salmeterol Xinafoate
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 255.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: endurance shuttle walk test; chronic obstructive pulmonary disease; fluticasone propionate; dyspnea; exercise endurance time; tiotropium; salmeterol; exercise inspiratory capacity; quality of life

Summary:

      The objective of this study is to demonstrate that, when added to tiotropium (TIO),
      fluticasone propionate/salmeterol combination (FSC) DISKUS 250/50 significantly increases
      exercise endurance time (EET) in the endurance shuttle walk test (ESWT), compared to TIO
      alone. Male and female subjects at least 40 years of age with a diagnosis of Chronic
      Obstructive Pulmonary Disease (COPD) are eligible. Subjects will be screened and consented at
      or during a 6-week (wk) period prior to visit (V)1. The 4-wk run-in period begins immediately
      after V1, when subjects receive open-label TIO plus as-needed relief inhaler (identical
      formulations called albuterol in the US and salbutamol in Canada). At V2, subjects will
      perform an incremental shuttle walk test (ISWT) to establish their maximal walk response. The
      first ESWT will occur at V3. Subjects must demonstrate an EET of ≤20 min that is reproducible
      (EET from V3 and V4 varying by ≤2 min). Eligible subjects are then randomized at V5 to either
      FSC 250/50mcg DISKUS twice daily plus open label TIO 18 mcg daily, or placebo DISKUS twice
      daily plus open label TIO 18 mcg daily for the 4-wk treatment period. The last study visit is
      V6. The primary efficacy measure is the difference between the EET at V6 (wk-8) vs. V4 (wk-3;
      the last ESWT done before randomized study drug is given). Secondary efficacy measures
      include V6 vs. V4 comparisons in exercise dyspnea scale (EDS), exercise inspiratory capacity
      (EIC) and cardio-respiratory measurements (CRM), and V6 vs. V5 comparisons in dyspnea related
      to activities of daily living (baseline dyspnea index and transition dyspnea index
      interviewer-administered [BDI-TDI]) and quality of life (Chronic Respiratory Disease
      Questionnaire Self-administered Standardized [CRQ-SAS]). The safety measure will be an
      assessment of adverse events. We will also attempt to validate prospectively the minimal
      clinically-important difference (MCID) for a change in the EET through correlation with
      dyspnea and quality of life results.
    

Eligibility criteria:

        Inclusion Criteria:

        Subjects eligible for enrolment in the study must meet all of the following criteria at V1.

          -  Consent: A signed and dated written informed consent must be obtained from the subject
             and/or subject's legally acceptable representative prior to study participation.

          -  Age: at least 40 yr of age

          -  Sex: Male or Female

        Females are eligible to participate only if they are currently not pregnant and not
        lactating. In addition, female subjects should not be enrolled if they plan to become
        pregnant during the time of study participation. A female is otherwise 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,

          -  child-bearing potential, has a negative pregnancy test (urine) at screening, and is
             committed to the consistent and correct use of an acceptable method of birth control,
             starting at V2, throughout the clinical trial, and for a period after the trial to
             account for elimination of the drug (minimum of six days), as defined by at least one
             of the following:

          -  use of implants of levonorgestrel or etonogestrel

          -  percutaneous contraceptive patches

          -  use of injectable progestogen

          -  use of oral contraceptive (either combined estrogen/progestin or progestin only)

          -  use of any intrauterine device (IUD) with published data showing that the highest
             expected failure rate is less than 1% per yr

          -  male partner is sterile (vasectomy with documentation of azoospermia; note that a
             verbal report of azoospermia is acceptable) and is the sole sexual partner for that
             female subject prior to the female subject's entry into the study

          -  double-barrier method; condom or occlusive cap (diaphragm or cervical/vault caps) plus
             spermicide

          -  abstinence: if not sexually active, must commit to complete abstinence from
             intercourse

        Female subjects, with the exception of those who are post-menopausal or surgically sterile,
        will undergo urine pregnancy tests approximately 7 days prior to first dose and
        approximately monthly.

          -  Diagnosis: An established clinical history of COPD in accordance with the definition
             of the American Thoracic Society (ATS).

          -  Severity of Disease: FEV1 post-albuterol/salbutamol at least 30 to no more than 80% of
             predicted normal and FEV1/FVC ratio post-albuterol/salbutamol of no more than 0.70
             based on NHANES III reference values. Note that identical formulations of short-acting
             beta-agonist are called albuterol in the US and salbutamol in Canada.

          -  Smoking History: A history of smoking at least 10 pack-yr is required. Pack-yr are
             defined as the number of packs of cigarettes smoked per day multiplied by the number
             of yr smoked. Please note that both current and previous smokers are eligible for this
             study. Previous smoking is defined as no smoking for at least 6 months prior to
             consent; subjects are otherwise considered "current" smokers.

          -  CXR: Chest radiograph, within 1 yr prior to consent, without findings suspected to
             represent an active, clinically-significant process other than those believed to be
             related to uncomplicated COPD.

          -  Use of TIO: A history of using TIO with compliance at least 80% starting at least 14
             days prior to V1, and ending 24 hr prior to V1, is required. Please note that any
             subject whose medical history precludes the safe use of TIO (such as significant
             narrow-angle glaucoma, known urinary retention, etc) should not be started on TIO for
             the purpose of this study.

        Exclusion Criteria:

        Subjects meeting any of the following criteria at V1 must not be enrolled in the study:

          -  Asthma: A current diagnosis of asthma.

          -  Other Diseases/Abnormalities: Any significant disease that, in the opinion of the
             investigator, would put the safety of the subject at risk through study participation,
             or which would affect the efficacy analysis if the disease/condition exacerbated
             during the study. Previously diagnosed cancer is considered a significant disease
             unless it is in complete remission for 2 yr (no evidence of tumor burden) at V1.
             Localized carcinomas of the skin that have been resected for cure are not
             exclusionary.

          -  Other Respiratory Disorders: Subject had lung resection surgery (e.g., lung volume
             reduction surgery or lobectomy) within 1 yr of V1 or has a significant respiratory
             disorder other than COPD (e.g., lung cancer, sarcoidosis, active tuberculosis,
             bronchiectasis, pulmonary fibrosis, sleep apnea, cystic fibrosis, or
             alpha-1-antitrypsin deficiency) that, in the opinion of the investigator, would put
             the safety of the subject at risk through study participation, or which would affect
             the efficacy analysis if the disease/condition exacerbated during the study.

          -  Acute Exacerbation of COPD: active disease within the past 6 wk. For the purpose of
             this study, an acute exacerbation of COPD will be identified using the following
             criteria [Anthonisen, 1987; Burge, 2003; Anzueto, 2009]: either

          -  worsening of two or more of the following "major" symptoms for at least two
             consecutive days:

          -  dyspnea

          -  sputum volume

          -  sputum purulence or

          -  worsening of any one major symptom together with any one of the following "minor"
             symptoms for at least two consecutive days:

          -  sore throat

          -  nasal discharge or nasal congestion

          -  fever without other cause

          -  increased cough or wheeze.

          -  Pulmonary Rehabilitation: Participation in the early, active phase of a Pulmonary
             Rehabilitation Program. For the purpose of this study, the "early, active" phase of
             pulmonary rehabilitation consists of sessions, scheduled on a regular and frequent
             basis (generally more than bi-weekly and for a total duration of at least 4 wk), held
             at an institution or at home, that include exercise training among interventions such
             as education and psychosocial support. Not included as the "early, active" phase of
             pulmonary rehabilitation are reinforcement or maintenance sessions that follow an
             "early, active" phase with interactions that are less frequent and less intense but
             may be scheduled for a longer total duration such as 6 months to 1 yr.

          -  12-Lead ECG: Potential subjects are excluded if they have a functioning cardiac
             pacemaker. Otherwise, the investigator will determine the clinical significance of any
             ECG abnormality, and whether it precludes the potential subject from entering the
             study.

          -  Drug Allergy: Any adverse reaction including immediate or delayed hypersensitivity to
             any beta2-agonist, sympathomimetic drug, corticosteroid (intranasal, inhaled, or
             systemic including any components of the formulations [e.g. lactose or milk protein]),
             or atropine or its derivatives, including ipratropium or tiotropium.

          -  Body Mass Index (BMI): A BMI of 40 kg/m2 or higher.

          -  Use of ritonavir, ketoconazole or other potent inhibitors of CYP3A4: If any of these
             medications are used prior to V1, they must be stopped at V1 if indicated.

          -  Other Exclusionary medications: If any of the following medications are used prior to
             V1, they must be stopped as specified below.

        (Medication, Washout period prior to V1) Any Investigational Drug, 30 days Oral or
        parenteral corticosteroids, 30 days ICS, 30 days ICS/LABA combination products (e.g.,
        ADVAIR, Symbicort), 30 days Theophylline, 7 days Tiotropium, 24 hr LABA (e.g. formoterol or
        salmeterol), 12 hr Short-acting beta-agonists (e.g., albuterol or salbutamol), 6 hr
        Ipratropium or ipratropium-containing combination products (e.g., Combivent), 6 hr Oral
        beta-agonists, 6 hr

          -  Long-Term Oxygen Therapy (LTOT): Subject is on LTOT and is receiving supplemental
             oxygen more frequently than nocturnal-only.

          -  Affiliation with investigator site: Subject is a study Investigator, sub-Investigator,
             study coordinator, or employee of a participating Investigator or immediate family
             member of the aforementioned.