copd is characterized by persistent airflow obstruction1 caused by exposure to irritants including cigarette smoke , dust , and fumes . to decrease the associated morbidity and mortality,2 given the regulatory barriers that are easiest to meet by improvement in lung function , the bulk of research is being directed towards the development of new bronchodilator and inhaled corticosteroid ( ics ) medications . according to the latest gold ( global initiative for chronic obstructive lung disease ) guidelines,3 a combination of ics , long - acting 2 agonist ( laba ) , and long - acting muscarinic receptor antagonist ( lama ) can be used for group d copd patients who are at high risk for exacerbations . group d patients are symptomatic and usually have a forced expiratory volume in 1 second ( fev1 ) of < 50% of the predicted value , two or more exacerbations within the last year , and/or one or more hospitalizations for copd exacerbations . the recommendation is based on a few studies showing the superiority of the ics / lama / laba combinations4,5 as compared to monotherapy alone , in the level of bronchodilation , dyspnea score change , and use of rescue medications . the concept of combining different bronchodilators in a single inhaler is an attractive one as it minimizes the number of copd medications that the patient takes on a daily basis and thus may boost patient compliance . however , the challenge in combining medications of different classes in a single drug delivery device is ensuring the bio - stability of the individual compounds . triple - combination therapies such as tiotropium added to salmeterol / fluticasone and glycopyrronium added to salmeterol / fluticasone6 have been evaluated , there are few combined or  closed triple therapies which are currently in development / available in the world as shown in table 1 . while laba / lama combinations for copd have become available in the us , there are currently no fixed - dose  closed triple thus , there has been longstanding interest in the development of triple - combination therapies for severe and very severe copd in the us , in keeping with the current gold guidelines . umeclidinium / fluticasone furoate / vilanterol ( umec / ff / vi ) is one such triple - combination therapy currently under development with some completed and several ongoing clinical trials . the purpose of this review paper is to highlight findings from these studies , including safety and efficacy data , while speculating on the role of this therapy in current treatment for copd . umec is an lama , vi is an laba , and ff is an ics . umec / vi and ff / vi are already being marketed as anoro ellipta and breo ellipta , respectively , by glaxosmithkline ( gsk ) . in isolated human bronchial strips , this antagonism is slowly reversible in a concentration - dependent manner.7 the time to 50% restoration of contraction at 10 nm is about 381 versus 413 minutes for tiotropium bromide . thus , umec is a potent anticholinergic agent that shows slow functional reversibility at the human m3 muscarinic receptor . studies of oral vi have shown it to be well tolerated up to doses of 500 g as a single administration in healthy men.8 a study9 of inhaled vi in asthma at a dose of 25 g once a day has shown it to be well tolerated with the commonest side effects reported being nasopharyngitis , headache , upper respiratory tract infection , and oropharyngitis . in yet another study conducted in healthy japanese men,10 single inhaled doses of vi of 50 g were found to be safe and well tolerated with no deaths or serious adverse events reported . thus , the low dose of inhaled vi which is used therapeutically is unlikely to produce unexpected systemic toxicity in copd patients . it is structurally related to fluticasone propionate , but with a distinct chemical and pharmacological profile . ff was found to be more potent than other glucocorticoids for preserving epithelial integrity and reducing epithelial permeability in response to protease- and mechanical - induced cell damage11 and was also found to have greater tissue retention than other glucocorticoids . pharmacokinetics of the triple therapy of umec / ff / vi12 has been studied in healthy volunteers . this triple therapy also called the  closed triple  is being developed by gsk and will be administered in a single inhaler ( ellipta dry powder device ) . two single - center studies12 assessed the systemic exposure , systemic pharmacodynamics ( pd ) , and safety profile of the closed triple therapy of umec / ff / vi compared with dual therapies . both studies were randomized , single - dose , crossover trials with study 1 being double - blind and study 2 being open - label . participants were randomized to receive four consecutive inhalations ( each administered as a single dose ) via an ellipta dry powder inhaler in the following ways . in study 1 ( ctt116415/nct01691547 ) , ff / umec / vi at total doses of 400/500/100 g , ff / umec 400/500 g , umec / vi 500/100 g , and ff / vi 400/100 g were compared . in study 2 ( 200587/nct01894386 ) , ff / umec / vi at total doses of 400/500/100 g or 400/250/100 g , ff / vi 400/100 g , and umec / vi 250/100 g were compared . of 88 subjects , 95% completed both studies . total systemic exposure was similar for the triple therapy of umec / ff / vi compared with ff / vi and umec / vi . thus , these studies showed that the closed triple therapy of umec / ff / vi was as safe as the currently marketed therapies of umec / vi ( marketed as anoro ellipta ) and ff / vi ( marketed as breo ellipta ) . in addition , the systemic exposure to the individual components showed no clinically significant differences when administered as triple versus dual therapy . two randomized studies have been conducted to study the safety and efficacy of umec added to ff / vi ( nct01957163 ; nct02119286 ) . both of these were 12-week , double - blind , placebo - controlled , parallel - group , multicenter studies and evaluated the safety and efficacy of umec ( 62.5 and 125 g ) added to ff / vi ( 100/25 g ) in copd.13 patients ( n=1,238 ) were randomized 1:1:1 to treatment with once - daily blinded umec 62.5 g , umec 125 g , or placebo ( pbo ) added to open - label ff / vi 100/25 g . inclusion criteria were age 40 years , diagnosis of copd , at least a 10 pack - years smoking history , pre- and post - salbutamol ( albuterol ) , fev1/forced vital capacity ratio of < 0.7 and predicted fev1 70% , and a modified medical research council dyspnea scale score 2 . subjects with asthma or other known respiratory disease , hospitalization in the prior 12 weeks for copd or pneumonia , pregnancy , or use of long - term oxygen therapy were excluded . the secondary end point was 06 hours post - dose weighted mean fev1 at day 84 . quality of life was reported using st george s respiratory questionnaire ( sgrq ) . in both studies , the primary and secondary end points were met ; the trough fev1 was significantly improved on day 85 with umec + ff / vi ( 62.5 and 125 g ) versus pbo + ff / vi ( range : 0.1110.128 l , p<0.001 ) as was 06 hours post - dose weighted mean fev1 on day 84 ( range : 0.1350.153 l , p<0.001 ) . improvements in sgrq were not seen consistently across both studies or with both doses of umec . further details about adverse effects with the triple - combination therapy are included in the  safety and tolerability  section . there are some additional studies which are currently underway evaluating the safety and efficacy of the triple therapy of umec / ff / vi . the triple combination of umec / ff / vi has been found to be generally well tolerated . six total deaths were reported in both studies , nct01957163 and nct02119286 , but were not considered related to the study treatment . of note , all treatment regimens had both inhaled  agonists and corticosteroids , and therefore , side effect differences would only be expected for the variance in umec use and dose that were evaluated in primary licensing studies.14,15 plan to file a new drug application in the us for the once - daily closed triple - combination therapy , ff / umec / vi , for patients with copd by the end of 2016 . the companies expect an eu regulatory submission of the closed triple - combination therapy for copd by the end of 2016 as well.16 one of the benefits of a triple combination of an ics / laba / lama is the potential improvement in patient compliance due to the need to take fewer inhalers . as triple therapy with ics / laba / lama is recommended for copd patients at high risk for exacerbations , this should in turn translate into fewer copd exacerbations , and consequently fewer copd - related hospitalizations . this is particularly important since the number of inhalers filled on average in the us is < 40% of that prescribed.17,18 on the other hand , the need for continued steroid use in severe copd patients with a history of exacerbations , on laba and lama therapy , has been called into question . in a recent study , in patients with severe copd on tiotropium + salmeterol , the risk of moderate or severe exacerbations was similar among those who discontinued ics and those who continued ics.19 there was , however , a greater decrease in lung function during the final step of glucocorticoid withdrawal . moreover , laba / lama combination inhalers have been shown to be superior to laba / ics in one recent clinical trial,20 further calling into question the necessity of an inhaled ics in copd treatment regimens . thus , while the initiation of triple therapy with ics / laba / lama in copd patients at high risk for exacerbations is appropriate , the landscape of clinical use is changing . the clinical explosion in use of the first long laba / ics combination salmeterol / fluticasone fumarate ( advair ) occurred at a time of limited competition . although some physicians at the time predicted its failure since monotherapy of laba and ics was already available , the primary care physician community drove use . a medication that could define if dyspnea was likely of pulmonary airways origin was welcomed . in contrast , airways disease patients are almost always responsive to combinations of any two components of an laba / lama / ics regimen because these drugs and their devices have been required to enter the us food and drug administration clinical trials arena together , there still remains no generic long - acting bronchodilator on the us market . the major reason for noncompliance with inhaled medications for copd is the cost of medication and/or copayments . with scheduled arrival of generic long - acting bronchodilators that will likely be less expensive within the life cycle of umec / ff / vi , few individuals believe that uptake will be rapid unless an aggressive price reduction from other combination bronchodilators accompanies the product launch . most of the current focus in drug development for copd has been on producing newer bronchodilators or combining bronchodilators in the same drug delivery device . with failure of large trials to significantly change mortality in copd despite enhancement of populations for cardiovascular disease , the use of lama / laba / ics medications is viewed at one level as an expenditure for quality - of - life improvements , particularly for dyspnea . therefore , compliance with medication that is used for improving quality of life may fit within the domain of the patient . the second indication that is outside of the patient domain is to decrease exacerbations that drive cost to both patients and hospital systems . as more health systems generate vertical models that require cost sharing for poor outcomes , the cost of triple - combination medications may be small in the relative cost of copd . therefore , the success of umec / ff / vi likely resides within health systems . for that reason , the upcoming studies on triple therapy for copd exacerbation reduction compared to dual therapies are important . until we can develop disease - modifying therapies for copd , the inhaler world keeps getting more crowded with combinations of laba , lama , and ics preparations . current studies of the closed triple therapy of umec / ff / vi reveal it to be a promising new treatment for copd patients who are at high risk for exacerbations . additional studies are underway to further delineate the impact of this therapy on lung function , exacerbation frequency , and quality of life . if approved for marketing , it will be an important addition to the treatment regimen for copd , will boost patient compliance , and may decrease the risk of hospitalizations due to copd exacerbations .
copd is characterized by persistent airflow obstruction caused by exposure to irritants including cigarette smoke , dust , and fumes . according to the latest gold ( global initiative for chronic obstructive lung disease ) guidelines , 
 a combination of inhaled corticosteroids , long - acting 2 agonists , and long - acting muscarinic receptor antagonists can be used for group d copd patients who are at high risk for exacerbations . 
 umeclidinium / fluticasone furoate / vilanterol is one such triple - combination therapy currently under development with some completed and several ongoing clinical trials . 
 this review paper summarizes the pharmacologic profiles of these medications and highlights findings from clinical trials , including safety and efficacy data , while speculating on the role of this therapy in current treatment for copd .