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Study to Evaluate the Effect of Fluticasone Furoate/Vilanterol on Survival in Subjects With Chronic Obstructive Pulmonary Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01313676
Recruitment Status : Completed
First Posted : March 14, 2011
Results First Posted : August 9, 2016
Last Update Posted : August 6, 2018
Information provided by (Responsible Party):

Tracking Information
First Submitted Date  ICMJE February 3, 2011
First Posted Date  ICMJE March 14, 2011
Results First Submitted Date  ICMJE March 10, 2016
Results First Posted Date  ICMJE August 9, 2016
Last Update Posted Date August 6, 2018
Actual Study Start Date  ICMJE January 25, 2011
Actual Primary Completion Date July 15, 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 18, 2016)
Number of Participants With Death (Both on and Off Treatment) Due to Any Cause, Time up to or on the Pre-determined Common End Date [ Time Frame: From the date of randomization until date of death due to any cause (average of 2 study years) ]
Death from any cause: which occurred from the day of starting IP until the Commone End Date (CED). Common End Date (CED) is the study end date that was pre determined where approximately 1000 deaths would have occurred in the Intent-toTreat Efficacy (ITT-E) Population. Only deaths which occurred on or before the CED were used for the primary analysis. Those who had not died by CED, but who were known to be alive on or after the CED, were censored at the CED. Cox Proportional Hazards (PH) Model was adjusted for age, and gender, including all 4 arms. A hazard ratio of less than 1 indicates a lower death rate versus placebo or other arm. ITT-E Population consisted of all participants in the Safety Population (i.e. randomized to IP and who received at least one dose of IP), with the exception of those recruited at sites that were closed.
Original Primary Outcome Measures  ICMJE
 (submitted: March 10, 2011)
all cause mortality [ Time Frame: approx 15 to 44 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 18, 2016)
  • Decline in Forced Expiratory Volume in 1 Second (FEV1) [ Time Frame: From start date of IP until IP stop date + 1 (assessed up to 4 years) ]
    FEV1 is a measure of lung function and is defined as the maximal amount of air that can be forcefully exhaled in one second. The effect of treatment on decline of post bronchodilator FEV1 recorded during the treatment period was analyzed using a particular form of a mixed effect model - a random coefficients model. FEV1 was fitted as the response variable with treatment group, age, gender, baseline FEV1 and time on treatment as fixed effects. Time on treatment was treated as a continuous variable. This model allowed for an initial increase in FEV1, but then tested the difference in slopes from the first post-baseline measurement which was at 3 months. A negative slope indicates a decline. A positive treatment difference indicates a slower rate of decline vs Placebo or Component. Only participants with at least one on-treatment post-bronchodilator FEV1 measurement were analyzed.
  • Number of Participants With First On-treatment Cardiovascular (CV) Composite Events Occured on or Before Common End Date [ Time Frame: From the start of IP to first on treatment CV event till 7 days after the last dose of IP (average of 2 study years) ]
    On-treatment CV composite event is comprised of the first event that is adjudicated as on-treatment CV death, myocardial infarction, stroke, unstable angina, or transient ischemic attack experienced by a participant. The events that occurred no more than 7 days after the participants last dose of IP are considered as on-treatment adverse events. Common end date is the study end date where approximately 1000 deaths would have occurred in the ITT-E Population. Cox PH Model was used to assess time to first on-treatment CV composite event. Cox PH Model was adjusted for age, gender and indicators of ischemic and vascular disease, including all four treatment arms. A hazard ratio less than 1 indicates a lower risk of a first CV event rate versus placebo or any arm.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 10, 2011)
  • FEV1 rate of decline [ Time Frame: approx 15 to 44 months ]
  • Time to cardiovascular composite endpoint [ Time Frame: approx 15 to 44 months ]
    Time to cardiovascular on treatment death, MI, stroke, unstable angina or TIA. All events will be adjudicated by an independent adjudication committee.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Study to Evaluate the Effect of Fluticasone Furoate/Vilanterol on Survival in Subjects With Chronic Obstructive Pulmonary Disease
Official Title  ICMJE A Clinical Outcomes Study to Compare the Effect of Fluticasone Furoate/Vilanterol Inhalation Powder 100/25mcg With Placebo on Survival in Subjects With Moderate Chronic Obstructive Pulmonary Disease (COPD) and a History of or at Increased Risk for Cardiovascular Disease
Brief Summary The purpose of this study is to determine if fluticasone furoate/vilanterol improves survival in patients with chronic obstructive pulmonary disease with a history of or increased risk of heart disease.
Detailed Description

Despite a potential link between the pathogenetic mechanisms involved in Chronic Obstructive Pulmonary Disease (COPD) and atherosclerotic cardiovascular disease, there are no currently approved therapies for patients with COPD that have clearly shown an additional beneficial effect in patients with cardiovascular comorbidities. The TOwards a Revolution in COPD Health (TORCH) study assessed the impact of the inhaled corticosteroid (ICS) fluticasone propionate (FP) in combination with the long-acting beta agonist (LABA), salmeterol (SAL), in reducing all-cause mortality. TORCH demonstrated a 17.5% reduction on all-cause mortality with salmeterol-fluticasone propionate combination (SFC) compared with placebo (HR=0.825, 95% CI (0.681, 1.002), p=0.052) in the entire COPD population with disease severity form moderate to very severe. A post hoc analysis of the data restricted to those subjects with an forced expiratory volume in 1 second (FEV1) >=50% predicted with an apparent history of cardiovascular co-morbidities (defined as use at baseline of beta-blockers, angiotensin converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB), HMG CoA reductase inhibitors (i.e. statins) or a prior MI recorded at baseline) demonstrated a 49% reduction in the risk of dying within 96 weeks for the comparison of SFC with placebo. These post hoc data suggest the possibility of an ICS/LABA combination product to be of substantial benefit in COPD subjects with less severe airflow obstruction yet with increased cardiovascular risk.

The mechanism by which SFC appears to be associated with a greater reduction in mortality in these less severe COPD subjects with concomitant cardiovascular comorbidities is speculative at present, but could potentially in part be related to a lessening of the degree of inflammation in the systemic circulation, potential plaque stabilization and/or amelioration of arterial stiffness.

ICS/LABA combinations that are currently available require twice daily administration. A once daily ICS/LABA combination has the potential to improve patient compliance and as a result, overall disease management.

The purpose of this study is to prospectively evaluate the effect of the once daily ICS/LABA combination Fluticasone Furoate (FF)/Vilanterol (VI) on survival in subjects with moderate COPD (>=50 and =<70 % predicted FEV1 ) and a history of, or at increased risk for cardiovascular disease.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Pulmonary Disease, Chronic Obstructive
Intervention  ICMJE
  • Drug: fluticasone furoate/vilanterol
    100/25mcg given once daily via novel dry powder inhaler
  • Drug: fluticasone furoate
    100mcg given once daily via novel dry powder inhaler
  • Drug: vilanterol
    25mcg given once daily via novel dry powder inhaler
  • Other: Placebo
    placebo comparator once daily via novel dry powder inhaler
Study Arms  ICMJE
  • Experimental: fluticasone furoate/vilanterol
    Combination of both products in one inhaler
    Intervention: Drug: fluticasone furoate/vilanterol
  • Experimental: fluticasone furoate
    comparator of individual component
    Intervention: Drug: fluticasone furoate
  • Experimental: vilanterol
    comparator of individual component
    Intervention: Drug: vilanterol
  • Placebo Comparator: placebo
    once daily via inhaler
    Intervention: Other: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 29, 2016)
Original Estimated Enrollment  ICMJE
 (submitted: March 10, 2011)
Actual Study Completion Date  ICMJE July 15, 2015
Actual Primary Completion Date July 15, 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Type of subject: outpatient.
  • Informed consent: Subjects must give their signed and dated written informed consent to participate.
  • Gender: Male or female. Female subjects must be post-menopausal or using a highly effective method for avoidance of pregnancy. The decision to include or exclude women of childbearing potential may be made at the discretion of the investigator in accordance with local practice in relation to adequate contraception.
  • Age: >=40 and <=80 years of age at Screening (Visit 1).
  • Tobacco use: Subjects with a current or prior history of >=10 pack-years of cigarette smoking at screening (Visit 1). Previous smokers are defined as those who have stopped smoking for at least 6 months prior to Visit 1.
  • Airflow Obstruction:

Subjects with a measured post-albuterol/salbutamol forced expiratory volume in 1 second (FEV1)/(forced vital capacity)FVC ratio of <=0.70 at Screening (Visit 1).

Subjects with a measured post-albuterol/salbutamol FEV1 >=50 and <=70% of predicted normal values calculated using NHANES III reference equations [Hankinson, 1999; Hankinson, 2010] at Screening (Visit 1).

Post-bronchodilator spirometry will be performed approximately 15 minutes after the subject has self-administered 4 inhalations (i.e., total 400mcg) of albuterol/salbutamol via a metered dose inhaler (MDI )with a valved-holding chamber. The FEV1/FVC ratio and FEV1 percent predicted values will be calculated.

  • Symptoms of COPD: Subjects must score 2 or higher on the modified Medical Research Council Dyspnea scale (Visit 1)
  • Cardiovascular disease:

For patients >= 40 years of age: any one of the following:

Established (i.e. by clinical signs or imaging studies) coronary artery disease (CAD) Established (i.e. by clinical signs or imaging studies) peripheral vascular disease (PVD) Previous stroke Previous MI Diabetes mellitus with target organ disease OR

For patients >=60 years of age: any 2 of the following:

Being treated for hypercholesterolemia Being treated for hypertension Being treated for diabetes mellitus Being treated for peripheral vascular disease

Exclusion Criteria:

  • Pregnancy: Women who are pregnant or lactating.
  • Asthma: Subjects with a current diagnosis of asthma. (Subjects with a prior history of asthma are eligible if they also have a current diagnosis of COPD).
  • alpha 1-antitrypsin deficiency: Subjects with known alpha-1 antitrypsin deficiency as the underlying cause of COPD.
  • Other respiratory disorders: Subjects with active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, pulmonary fibrosis, pulmonary hypertension, interstitial lung diseases or other active pulmonary diseases.
  • Lung resection or transplantation: Subjects with lung volume reduction surgery within the 12 months prior to Screening or having had a lung transplant.
  • A moderate/severe COPD exacerbation that has not resolved at least 14 days prior to Visit 1 and at least 30 days following the last dose of oral corticosteroids (if applicable).
  • Current severe heart failure (New York Heart Association class IV). Subjects will also be excluded if they have a known ejection fraction of <30% or if they have an implantable cardioverter defibrillator (ICD).
  • Other diseases/abnormalities: Any life-threatening condition with life expectancy <3 years, other than vascular disease or COPD, that might prevent the subject from completing the study.
  • End stage chronic renal disease: Subjects will be excluded if on renal replacement therapy (hemodialysis or peritoneal).
  • Drug/food allergy: Subjects with a history of hypersensitivity to any of the study medications (e.g. beta-agonists, corticosteroid) or components of the inhalation powder (e.g. lactose, magnesium stearate). In addition, patients with a history of severe milk protein allergy that, in the opinion of the study physician, contraindicates the subject's participation will also be excluded.
  • Drug/alcohol abuse: Subjects with a known or suspected history of alcohol or drug abuse within the last 2 years.
  • Oxygen therapy: Subjects receiving treatment with long-term oxygen therapy (LTOT) or nocturnal oxygen therapy required for greater than 12 hours a day. Oxygen prn use (i.e. <=12 hours per day) is not exclusionary.
  • Questionable validity of consent: Subjects with a history of psychiatric disease, intellectual deficiency, poor motivation or other conditions that will limit the validity of informed consent to participate in the study or the potential compliance to study procedures.
  • Affiliation with investigator site: Study investigators, sub-investigators, study coordinators, employees of a participating investigator or immediate family members of the aforementioned are excluded from participating in this study.
  • Additional medication: Use of the following medications within the following time intervals prior to Visit 1 or during the study (unless otherwise specified):

Medication No use within the following time intervals prior to Screening or thereafter at any time during the study (unless otherwise specified) Inhaled Long acting beta-agonists (LABA) 48 hours ICS/LABA combination products 48 hours Inhaled corticosteroids 48 hours Tiotropium 1 week Systemic, Oral, parenteral, intra-articular corticosteroids 30 days (oral and systemic corticosteroids may be used to treat COPD exacerbations during the study) Cytochrome P450 3A4 strong inhibitors including but not limited to antiretrovirals (protease inhibitors) (e.g.Indinavir, Nelfinavir, Ritonavir, Saquinavir); Imidazole and Triazole anti-fungals (e.g. Ketaconazole, Itraconazole); Clarithromycin, Telithromycin, Amiodarone, and Nefazodone 6 weeks Grapefruit is allowed up to Visit 1, then limited to no more than one glass of grapefruit juice (250 mL/ 8 ounces) or one grapefruit per day Any other investigational drug 30 days or 5 half lives whichever is longer.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Australia,   Austria,   Belarus,   Belgium,   Bosnia and Herzegovina,   Bulgaria,   Canada,   Chile,   China,   Colombia,   Croatia,   Czechia,   France,   Georgia,   Germany,   Greece,   Hungary,   India,   Indonesia,   Israel,   Italy,   Japan,   Korea, Republic of,   Latvia,   Macedonia, The Former Yugoslav Republic of,   Malaysia,   Mexico,   Netherlands,   Philippines,   Poland,   Romania,   Russian Federation,   Serbia,   Slovakia,   South Africa,   Spain,   Taiwan,   Thailand,   Turkey,   Ukraine,   United Kingdom,   United States,   Vietnam
Removed Location Countries Czech Republic
Administrative Information
NCT Number  ICMJE NCT01313676
Other Study ID Numbers  ICMJE 113782
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party GlaxoSmithKline
Study Sponsor  ICMJE GlaxoSmithKline
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: GSK Clinical Trials GlaxoSmithKline
PRS Account GlaxoSmithKline
Verification Date August 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP