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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01313676
First received: February 3, 2011
Last updated: July 21, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Pulmonary Disease, Chronic Obstructive
Drug: fluticasone furoate/vilanterol
Drug: fluticasone furoate
Drug: vilanterol
Other: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • all cause mortality [ Time Frame: approx 15 to 44 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • FEV1 rate of decline [ Time Frame: approx 15 to 44 months ] [ Designated as safety issue: No ]
  • Time to cardiovascular composite endpoint [ Time Frame: approx 15 to 44 months ] [ Designated as safety issue: No ]
    Time to cardiovascular on treatment death, MI, stroke, unstable angina or TIA. All events will be adjudicated by an independent adjudication committee.


Estimated Enrollment: 16000
Study Start Date: January 2011
Estimated Study Completion Date: January 2015
Estimated Primary Completion Date: January 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: fluticasone furoate/vilanterol
Combination of both products in one inhaler
Drug: fluticasone furoate/vilanterol
100/25mcg given once daily via novel dry powder inhaler
Experimental: fluticasone furoate
comparator of individual component
Drug: fluticasone furoate
100mcg given once daily via novel dry powder inhaler
Experimental: vilanterol
comparator of individual component
Drug: vilanterol
25mcg given once daily via novel dry powder inhaler
Placebo Comparator: placebo
once daily via inhaler
Other: Placebo
placebo comparator once daily via novel dry powder inhaler

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.

  Eligibility

Ages Eligible for Study:   40 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.

  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: NCT01313676

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

No publications provided by GlaxoSmithKline

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01313676     History of Changes
Other Study ID Numbers: 113782
Study First Received: February 3, 2011
Last Updated: July 21, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
COPD
Cardiovascular disease
Novel Dry Powder Inhaler
Survival

Additional relevant MeSH terms:
Cardiovascular Diseases
Chronic Disease
Lung Diseases
Respiration Disorders
Pulmonary Disease, Chronic Obstructive
Lung Diseases, Obstructive
Disease Attributes
Respiratory Tract Diseases
Pathologic Processes
Fluticasone
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Asthmatic Agents
Respiratory System Agents
Therapeutic Uses
Dermatologic Agents
Anti-Allergic Agents
Anti-Inflammatory Agents

ClinicalTrials.gov processed this record on July 24, 2014