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

This study has been completed.
Sponsor:
Information provided by:
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01124422
First received: May 13, 2010
Last updated: January 19, 2012
Last verified: November 2011
  Purpose

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.


Condition Intervention Phase
Pulmonary Disease, Chronic Obstructive
Drug: fluticasone propionate/salmeterol inhalation powder DISKUS 250/50
Drug: tiotropium bromide inhalation powder HandiHaler
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Study of Fluticasone Propionate/Salmeterol DISKUS Combination Product 250/50 Mcg Twice Daily Plus Tiotropium 18 Mcg Daily Versus Placebo DISKUS Twice Daily Plus Tiotropium 18 Mcg Daily on Exercise Time and Physiological Parameters in Subjects With Chronic Obstructive Pulmonary Disease

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Mean Change in Exercise Endurance Time (EET) From Baseline (Week 3) to Week 8 [ Time Frame: Baseline (Week 3) and Week 8 ] [ Designated as safety issue: No ]
    EET is defined as the time taken by a participant to exert himself during an exercise. EET was calculated based on the Endurance Shuttle Walk test (ESWT). The ESWT is a standardized, externally controlled, constant-paced field test for the assessment of endurance capacity in participants with chronic lung disease. Change from Baseline in EET was calculated as the value at Week 8 minus the value at Baseline.


Secondary Outcome Measures:
  • Mean Change in Scores on the Exercise Dyspnea Scale (EDS) From Baseline (Week 3) to Week 8 [ Time Frame: Baseline (Week 3) and Week 8 ] [ Designated as safety issue: No ]
    EDS is used to measure the level of breathlessness due to exercise, assessed using a 10-point modified Borg scale at 2-minute intervals during the ESWT: 0=no difficulty in breathing at all, 10=maximal breathing difficulty (BD). The participant pointed to the level on the scale correlating with his BD, and the local study coordinator confirmed that level verbally to him. Change from Baseline was calculated as the value at Week 8 minus the value at Baseline. A dyspnea score/time slope was calculated by fitting a linear regression line to the dyspnea scores reported during the exercise tests.

  • Mean Change in EDS at Isotime From Baseline (Week 3) to Week 8 [ Time Frame: Baseline (Week 3) and Week 8 ] [ Designated as safety issue: No ]
    EDS at isotime (last common time point for an exercise assessment [i.e., last Borg score time point of the shortest exercise test for each participant]) was assessed using a 10-point modified Borg scale. Change from Baseline in EDS at isotime was calculated as the value at Week 8 minus the value at Baseline.

  • Mean Change in Pre-dose and Post-dose Resting Inspiratory Capacity (IC) From Baseline (Week 4) to Week 8 [ Time Frame: Baseline (Week 4) and Week 8 ] [ Designated as safety issue: No ]
    Resting IC is the volume of gas that can be taken into the lungs in a full inhalation at the resting position. The resting IC was measured before and after dosing. Change from Baseline in pre-dose resting IC was calculated as the pre-dose value at Week 8 minus the pre-dose value at Week 4. Change from Baseline in post-dose resting IC was calculated as the post-dose value at Week 8 minus the pre-dose value at Week 4.

  • Mean Change in Exercise Inspiratory Capacity (EIC) at the End of Exercise From Baseline (Week 3) to Week 8 [ Time Frame: Baseline (Week 3) and Week 8 ] [ Designated as safety issue: No ]
    EIC is the volume of gas that can be taken into the lungs in a full inhalation during exercise. Participants were asked to undergo the IC test every 2 minutes during exercise and at the end of the exercise, to follow changes in operational lung volumes that occured in association with exercise. Change from Baseline in EIC was calculated as the value at the end of exercise at Week 8 minus the value at the end of exercise at Baseline.

  • Mean Change in Flow of Oxygen (V'O2) Per Time Slope During the Course of the ESWT From Baseline (Week 3) to Week 8 [ Time Frame: Baseline (Week 3) and Week 8 ] [ Designated as safety issue: No ]
    The V'O2 was measured during the ESWT using the Oxycon Mobile System (OMS), a portable telemetric monitoring system consisting of an oxygen sensor allowing for breath-by-breath measurement of gas exchange parameters in the lungs. The V'O2 was collected in units of mL and then regressed over the conduct of the exercise test measured in minutes. The V'O2 per time slope was calculated for each participant (par.) by fitting a linear regression line to the V'O2 recorded for each par. during the ESWT. V'O2 per time slope results were compared between treatment groups as means of these regression lin

  • Mean Change in Flow of Carbon Dioxide (V'CO2) Per Time Slope During the Course of the ESWT From Baseline (Week 3) to Week 8 [ Time Frame: Baseline (Week 3) and Week 8 ] [ Designated as safety issue: No ]
    The amount of CO2 in the hemoglobin of the participants was measured during the ESWT using the OMS. The system consisted of a carbon dioxide sensor and allowed breath-by-breath measurement of pulmonary gas exchange parameters. The V'CO2 per time slope was calculated for each participant by fitting a linear regression line to the V'CO2 recorded for each participant during the ESWT. V'CO2 per time slope results were compared between treatment groups as means of these regression lines. Change from Baseline in V'CO2 per time slope was calculated as the value at Week 8 minus the value at Baseline.

  • Mean Change in Minute Ventilation (V'E) Per Time Slope During the Course of the ESWT From Baseline (Week 3) to Week 8 [ Time Frame: Baseline (Week 3) and Week 8 ] [ Designated as safety issue: No ]
    The V'E was measured in the participants during the ESWT using the OMS. The system consisted of a volume transducer, oxygen sensor, and carbon dioxide sensor and allowed breath-by-breath measurement of pulmonary gas exchange parameters. The V'E was collected in liters and then regressed over the conduct of the exercise test measured in minutes. The V'E per time slope was calculated for each participant by fitting a linear regression line to the V'E recorded for each participant during the ESWT. V'E per time slope results were compared between treatment groups as means of the regression lines.

  • Mean Change in Heart Rate (HR) Per Time Slope During the Course of the ESWT From Baseline (Week 3) to Week 8 [ Time Frame: Baseline (Week 3) and Week 8 ] [ Designated as safety issue: No ]
    HR is defined as the number of heartbeats per unit of time, typically expressed as beats per minute (bpm). It was measured during the ESWT using the OMS. The HR was collected in units of bpm and then regressed over the conduct of the exercise test measured in minutes. The HR per time slope was calculated for each participant by fitting a linear regression line to the HR recorded for each participant during the exercise test. HR per time slope results were compared between treatment groups as means of these regression lines.

  • Mean Change in Respiratory Exchange Ratio (RER) Per Time Slope During the Course of the ESWT From Baseline to Week 8 [ Time Frame: Baseline (Week 3) and Week 8 ] [ Designated as safety issue: No ]
    The respiratory exchange ratio was calculated as the ratio of VCO2 and VO2. The ratio of the amount of carbon dioxide and oxygen in the hemoglobin of the participants was measured during the ESWT using the OMS. The system consisted of oxygen and carbon dioxide sensors and allowed breath-by-breath measurement of pulmonary gas exchange parameters. Change from Baseline in RER was calculated as the value at Week 8 minus the value at Baseline.

  • Mean Change in Respiratory Rate (RR) Per Time Slope During the Course of the ESWT From Baseline (Week 3) to Week 8 [ Time Frame: Baseline (Week 3) and Week 8 ] [ Designated as safety issue: No ]
    RR is defined as the number of breaths taken within a set amount of time (typically within 60 secs). The RR of the participants was measured during the ESWT using the OMS. The system consisted of volume transducer oxygen and carbon dioxide sensors and allowed breath-by-breath measurement of pulmonary gas exchange parameters. The RR per time slope was calculated for each participant by fitting a linear regression line to the RR recorded for each participant during the ESWT. RR per time slope results were compared between treatment groups as means of these regression lines.

  • Mean Change in Respiratory Rate (RR) at Isotime During the Course of the ESWT From Baseline to Week 8 [ Time Frame: Baseline (Week 3) and Week 8 ] [ Designated as safety issue: No ]
    RR is defined as the number of breaths taken within a set amount of time (typically within 60 secs). The RR of the participants at isotime was measured during the ESWT using the OMS. Change from Baseline in RR at isotime was calculated as the value at Week 8 minus the value at Baseline.

  • Mean Change in Tidal Volume (VT) Per Time Slope During the Course of the ESWT From Baseline to Week 8 [ Time Frame: Baseline (Week 3) and Week 8 ] [ Designated as safety issue: No ]
    VT is the lung volume representing the normal volume of air displaced between normal inspiration and expiration when extra effort is not applied (normal value is approximately 500 mL or 7 mL/kg body weight). VT was measured during the ESWT using the OMS, consisting of volume transducer O2 and CO2 sensors and allowing breath-by-breath measurement of pulmonary gas exchange parameters. The participant's VT per time slope was calculated by fitting a linear regression line (RL) to their VT during the ESWT. VT per time slope results were compared between treatment groups as means of these RLs.

  • Mean Change in Tidal Volume (VT) at Isotime During the Course of the ESWT From Baseline to Week 8 [ Time Frame: Baseline (Week 3) and Week 8 ] [ Designated as safety issue: No ]
    VT is defined as the lung volume representing the normal volume of air displaced between normal inspiration and expiration when extra effort is not applied. The normal value is approximately 500 mL or 7 mL/kg body weight. The VT of the participants at isotime was measured during the ESWT using the OMS. Change from Baseline in VT at isotime was calculated as the value at Week 8 minus the value at Baseline.

  • Mean Change in HR Per Time Slope During the Course of the ESWT Using Pulse Oximetry From Baseline to Week 8 (Non-OMS Subgroup) [ Time Frame: Baseline (Week 3) and Week 8 ] [ Designated as safety issue: No ]
    HR was measured during the course of the ESWT in the non-OMS subgroup using pulse oximetry. The HR per time slope was calculated for each participant by fitting a linear regression line to the HR recorded for each participant during the ESWT. HR per time slope results were compared between treatment groups as means of these regression lines. Change from Baseline in HR was calculated as the value at Week 8 minus the value at Baseline.

  • Mean Change in Ratio of Respiratory Rate (RR) to Tidal Volume (VT) or RR/VT at Isotime During the Course of the ESWT From Baseline to Week 8 [ Time Frame: Baseline (Week 3) and Week 8 ] [ Designated as safety issue: No ]
    The RR and VT of the participants at isotime were measured during the ESWT using the OMS. The ratio of RR per VT (value of RR divided by value of VT) at isotime was calculated. Change from Baseline in RR/VT at isotime was calculated as the value at Week 8 minus the value at Baseline.

  • Mean Change in EIC at 2 to 3.5 Minutes During the Exercise Period From Baseline (Week 3) to Week 8 [ Time Frame: Baseline (Week 3) and Week 8 ] [ Designated as safety issue: No ]
    The EIC was measured at 2 to 3.5 minutes during the exercise period. Change from Baseline in EIC was calculated as the value at Week 8 minus the value at Baseline.

  • Mean Change in Scores on the Chronic Respiratory Disease Questionnaire Self-Administered Standardized (CRQ-SAS) Questionnaire From Week 4 to Week 8 [ Time Frame: Week 4 and Week 8 ] [ Designated as safety issue: No ]
    The CRQ-SAS, a self-administered tool used to assess health-related quality-of-life (HRQOL), consists of 20 questions (q.) in 4 domains: Dyspnea (5 q.), Fatigue (4 q.), Emotional Function (7 q.), and Mastery (4 q.). Participants rated their experience on a 7-point scale in response to each q.: 1 (maximum impairment) to 7 (no impairment); higher scores indicate better HRQOL. Individual q. were equally weighted, and domain scores (range=1-7) were calculated as the mean across the non-missing items within each domain (domain scores were calculated although an individual item score was missing).

  • Baseline Dyspnea Index (BDI) at Week 4 and Transition Dyspnea Index (TDI) at Week 8 [ Time Frame: BDI: Week 4; TDI: Week 8 ] [ Designated as safety issue: No ]
    The BDI-TDI is a multidimensional dyspnea measurement. The BDI, administered at Week 4, consisted of 3 items (functional impairment, magnitude of task in exertional capacity, and magnitude of effort) requiring recall over the previous 4 weeks. BDI scores ranged from 0 (very severe impairment) to 4 (no impairment); the summed total score = 0 to 12. The TDI, administered at Week 8 as a follow-up of the BDI, consisted of the same 3 items requiring recall over the previous 4 weeks. TDI scores ranged from -3 (major deterioration) to +3 (major improvement); the summed total score = -9 to 9.


Enrollment: 255
Study Start Date: July 2010
Study Completion Date: May 2011
Primary Completion Date: May 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: fluticasone propionate/salmeterol DISKUS 250/50 + tiotropium
This is the active DISKUS (that is, containing fluticasone propionate/salmeterol combination) + open-label tiotropium
Drug: fluticasone propionate/salmeterol inhalation powder DISKUS 250/50
Experimental comparator consisting of inhaled corticosteroid plus long-acting beta agonist combination also known as ADVAIR DISKUS
Drug: tiotropium bromide inhalation powder HandiHaler
Open-label drug also known as Spiriva HandiHaler
Placebo Comparator: placebo DISKUS + tiotropium
This is the DISKUS and excipient minus the active ingredient (which is fluticasone propionate/salmeterol combination) + open-label tiotropium
Drug: tiotropium bromide inhalation powder HandiHaler
Open-label drug also known as Spiriva HandiHaler

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   40 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01124422

  Show 25 Study Locations
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

No publications provided

Responsible Party: Cheri Hudson; Clinical Disclosure Advisor, GSK Clinical Disclosure
ClinicalTrials.gov Identifier: NCT01124422     History of Changes
Other Study ID Numbers: 113877
Study First Received: May 13, 2010
Results First Received: November 17, 2011
Last Updated: January 19, 2012
Health Authority: Canada: Health Canada
United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
endurance shuttle walk test
chronic obstructive pulmonary disease
fluticasone propionate
dyspnea
exercise endurance time
tiotropium
salmeterol
exercise inspiratory capacity
quality of life

Additional relevant MeSH terms:
Lung Diseases
Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Chronic Disease
Respiratory Tract Diseases
Disease Attributes
Pathologic Processes
Fluticasone
Tiotropium
Salmeterol
Anti-Inflammatory Agents
Therapeutic Uses
Pharmacologic Actions
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Dermatologic Agents
Anti-Allergic Agents
Parasympatholytics
Cholinergic Antagonists
Cholinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Adrenergic beta-2 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists
Adrenergic Agents

ClinicalTrials.gov processed this record on September 18, 2014