Fluticasone Propionate/Salmeterol Combination 250/50 DISKUS in the Exercise Endurance Time in Patients With Chronic Obstructive Pulmonary Disease

We postulate that adding fluticasone propionate/salmeterol combination DISKUS 250/50 (FSC) to tiotropium (TIO) will improve exercise endurance time (EET) and its clinical and physiologic correlates, based on the combination of the three different mechanisms of action represented. We propose to test this hypothesis by comparing outcomes of exercise testing (Endurance Shuttle Walk Test; ESWT) with FSC added to TIO compared to those on TIO alone.

The primary objective is to demonstrate that, when added to TIO, FSC significantly increases EET compared to TIO alone at Visit 6 (V6; week [wk]-8) vs. V4 (wk-3; the last ESWT before double-blind drug).

Secondary efficacy measures will be as follows. Exercise dyspnea scale (EDS), exercise inspiratory capacity (EIC) and cardio-respiratory measurements (CRM) will involve V6 vs. V4 comparisons. Dyspnea related to activities of daily living (ADLs) will be assessed using the baseline dyspnea index and transition dyspnea index interviewer-administered (BDI-TDI), and quality of life will be assessed using the Chronic Respiratory Disease Questionnaire Self-Administered Standardized (CRQ-SAS). The BDI-TDI and CRQ-SAS will be based on comparisons of data from V6 vs. V5. We will also attempt to validate prospectively the minimal clinically-important difference (MCID) for a change in the EET through correlation with dyspnea (Likert scale).

Safety evaluations will include the type, incidence and severity of adverse events.

This is a randomized, parallel-group study totalling 6 visits. Screening is at or up to 6 wk prior to V1, and includes a discussion of study procedures, a review of inclusion/exclusion criteria, collection of informed written consent, adjustment of medications and determination of spirometry pre- and post-albuterol/salbutamol. At V1, subjects meeting inclusion criteria will be enrolled, familiarized with the incremental shuttle walk test (ISWT), and given paper diaries.

The run-in will begin with the dispensing of open-label medications at the end of V1. During the 4-wk run-in, subjects will have 3 visits (V2-V4). Open-label TIO will be taken daily beginning after V1, and open-label relief inhaler (identical formulations called albuterol in the US and salbutamol in Canada) will be taken on an as-needed basis beginning after V1. Open-label medications will be withheld before V2, V3 and V4 (last dose of TIO, the morning of the day before the visit; last dose of albuterol/salbutamol, at least 6 hr before the start of the visit). At V2, subjects will be given open-label TIO, will undergo ISWT 2.5-hr post-TIO, and will be familiarized with the ESWT. At V3 and V4, subjects will be given open-label TIO, and will undergo ESWT 2.5-hr post-TIO. ESWT will be performed again at V4 only if the EET at V3 was ≤20 min. Subjects will be studied at V5 if the EET result from V4 is also ≤20 min and the EET from V3 and V4 vary from each other by ≤2 min; otherwise, subjects will be withdrawn. The ESWT from V4 will be used as the baseline EET for exercise-related outcomes because it will be the last ESWT done before double-blind study drug is given.

Open-label medications will be withheld before V5 and V6 (last dose of TIO the morning of the day before the visit; last dose of albuterol/salbutamol, at least 6 hr before the start of the visit). At V5, subjects will undergo spirometry, lung volumes and diffusing capacity, and will be randomized. Subjects will then be given open-label TIO and double-blind DISKUS study drug, and undergo spirometry and lung volumes 2 hr post-TIO/double-blind DISKUS study drug, and ESWT 2.5 hr post-dose. Per randomization, subjects will receive for 4 wk after V5, open-label TIO plus either FSC or placebo DISKUS. Double-blind DISKUS study drug will be withheld before V6 (last dose the evening of the day before the visit). V6 will be the last study visit, consisting of spirometry and lung volumes, followed by open-label TIO and double-blind DISKUS study drug, spirometry and lung volumes 2 hr post-dose, and the final ESWT 2.5 hr post-dose.

All study visits will begin with a check-up to determine eligibility for further study procedures. Details of the paper diary report will be reviewed after drug administration, V2 through V6. Immediately after review of the paper diary, BDI (at V5), TDI (at V6) and CRQ-SAS (V5 and V6) will be undertaken, and the post-dose study activities, as outlined above, will follow.

Final contact will be by telephone approximately 2 wk after V6 or Early Withdrawal. The total duration of the study will be 8 wk, including the 4 wk run-in and the 4 wk period of double-blind plus open-label treatment. There will also be a screening period of up to 6 wk prior to V1, and the 2-wk period after the final study visit for phone call follow-up.

Subjects at a subset of sites will undergo EIC and CRM during each ESWT using portable telemetric monitoring (Oxycon Mobile; CareFusion, San Diego, CA).

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.