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).
