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
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 255
- 试验地点
- 1
- 主要终点
- Mean Change in Exercise Endurance Time (EET) From Baseline (Week 3) to Week 8
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 40 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subjects eligible for enrolment in the study must meet all of the following criteria at V
- •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.
排除标准
- •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 V
- •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:
- •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.
研究组 & 干预措施
fluticasone propionate/salmeterol DISKUS 250/50 + tiotropium
This is the active DISKUS (that is, containing fluticasone propionate/salmeterol combination) + open-label tiotropium
干预措施: fluticasone propionate/salmeterol inhalation powder DISKUS 250/50 (Drug)
fluticasone propionate/salmeterol DISKUS 250/50 + tiotropium
This is the active DISKUS (that is, containing fluticasone propionate/salmeterol combination) + open-label tiotropium
干预措施: tiotropium bromide inhalation powder HandiHaler (Drug)
placebo DISKUS + tiotropium
This is the DISKUS and excipient minus the active ingredient (which is fluticasone propionate/salmeterol combination) + open-label tiotropium
干预措施: tiotropium bromide inhalation powder HandiHaler (Drug)
结局指标
主要结局
Mean Change in Exercise Endurance Time (EET) From Baseline (Week 3) to Week 8
时间窗: Baseline (Week 3) and Week 8
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.
次要结局
- Mean Change in Scores on the Exercise Dyspnea Scale (EDS) From Baseline (Week 3) to Week 8(Baseline (Week 3) and Week 8)
- Mean Change in Pre-dose and Post-dose Resting Inspiratory Capacity (IC) From Baseline (Week 4) to Week 8(Baseline (Week 4) and Week 8)
- Mean Change in Exercise Inspiratory Capacity (EIC) at the End of Exercise From Baseline (Week 3) to Week 8(Baseline (Week 3) and Week 8)
- Mean Change in EDS at Isotime From Baseline (Week 3) to Week 8(Baseline (Week 3) and Week 8)
- 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(Baseline (Week 3) and Week 8)
- Mean Change in Minute Ventilation (V'E) Per Time Slope During the Course of the ESWT From Baseline (Week 3) to Week 8(Baseline (Week 3) and Week 8)
- Mean Change in Heart Rate (HR) Per Time Slope During the Course of the ESWT From Baseline (Week 3) to Week 8(Baseline (Week 3) and Week 8)
- Mean Change in Respiratory Rate (RR) Per Time Slope During the Course of the ESWT From Baseline (Week 3) to Week 8(Baseline (Week 3) and Week 8)
- Mean Change in Respiratory Rate (RR) at Isotime During the Course of the ESWT From Baseline to Week 8(Baseline (Week 3) and Week 8)
- Mean Change in Tidal Volume (VT) Per Time Slope During the Course of the ESWT From Baseline to Week 8(Baseline (Week 3) and Week 8)
- Mean Change in Flow of Oxygen (V'O2) Per Time Slope During the Course of the ESWT From Baseline (Week 3) to Week 8(Baseline (Week 3) and Week 8)
- Mean Change in Respiratory Exchange Ratio (RER) Per Time Slope During the Course of the ESWT From Baseline to Week 8(Baseline (Week 3) and Week 8)
- Mean Change in Tidal Volume (VT) at Isotime During the Course of the ESWT From Baseline to Week 8(Baseline (Week 3) and Week 8)
- Mean Change in HR Per Time Slope During the Course of the ESWT Using Pulse Oximetry From Baseline to Week 8 (Non-OMS Subgroup)(Baseline (Week 3) and Week 8)
- 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(Baseline (Week 3) and Week 8)
- Mean Change in EIC at 2 to 3.5 Minutes During the Exercise Period From Baseline (Week 3) to Week 8(Baseline (Week 3) and Week 8)
- Mean Change in Scores on the Chronic Respiratory Disease Questionnaire Self-Administered Standardized (CRQ-SAS) Questionnaire From Week 4 to Week 8(Week 4 and Week 8)
- Baseline Dyspnea Index (BDI) at Week 4 and Transition Dyspnea Index (TDI) at Week 8(BDI: Week 4; TDI: Week 8)