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Can inhaled fluticasone alone or in combination with salmeterol reduce systemic inflammation in chronic… Sin, Don D; Man, SF P; Marciniuk, Darcy D; Ford, Gordon; FitzGerald, Mark; Wong, Eric; York, Ernest; Mainra, Rajesh R; Ramesh, Warren; Melenka, Lyle S; Wilde, Eric; Cowie, Robert L; Williams, Dave; Rousseau, Roxanne Feb 6, 2006

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ralssBioMed CentBMC Pulmonary MedicineOpen AcceStudy protocolCan inhaled fluticasone alone or in combination with salmeterol reduce systemic inflammation in chronic obstructive pulmonary disease? – study protocol for a randomized controlled trial [NCT00120978]Don D Sin*1, SF Paul Man1, Darcy D Marciniuk2, Gordon Ford5, Mark FitzGerald1, Eric Wong3, Ernest York4, Rajesh R Mainra6, Warren Ramesh7, Lyle S Melenka8, Eric Wilde9, Robert L Cowie5, Dave Williams10, Roxanne Rousseau1 and the ABC (Advair, Biomarkers in COPD) InvestigatorsAddress: 1Department of Medicine (Respiratory Division), University of British Columbia, Vancouver, Canada, 2Department of Medicine, University of Saskatchewan, Saskatoon, Canada, 3Department of Medicine, University of Alberta, Edmonton, Canada, 4Wetaskiwin General Hospital, Wetaskiwin, Canada, 5Department of Medicine, University of Calgary, Calgary, Canada, 6Lions Gate Hospital, North Vancouver, Canada, 7Royal Alexandra Hospital, Edmonton, Canada, 8Grey Nuns Hospital, Edmonton, Canada, 9Lethbridge General Hospital, Lethbridge, Canada and 10Matsqui-Sumas-Abbotsford General Hospital, Abbotsford, CanadaEmail: Don D Sin* - dsin@mrl.ubc.ca; SF Paul Man - pman@providencehealth.bc.ca; Darcy D Marciniuk - darcy.marciniuk@usask.ca; Gordon Ford - Gordon.Ford@CalgaryHealthRegion.ca; Mark FitzGerald - markf@interchange.ubc.ca; Eric Wong - ewong@ualberta.ca; Ernest York - eyork@telusplanet.net; Rajesh R Mainra - mainra@shaw.ca; Warren Ramesh - wramesh@attcanada.net; Lyle S Melenka - lsmmd@shaw.ca; Eric Wilde - erwilde@telusplanet.net; Robert L Cowie - cowie@ucalgary.ca; Dave Williams - Dave.Williams@fraserhealth.ca; Roxanne Rousseau - RRousseau@mrl.ubc.ca* Corresponding author    AbstractBackground: Systemic inflammation is associated with various complications in chronicobstructive pulmonary disease including weight loss, cachexia, osteoporosis, cancer andcardiovascular diseases. Inhaled corticosteroids attenuate airway inflammation, reduceexacerbations, and improve mortality in chronic obstructive pulmonary disease. Whether inhaledcorticosteroids by themselves or in combination with a long-acting β2-adrenoceptor agonistrepress systemic inflammation in chronic obstructive pulmonary disease is unknown. The AdvairBiomarkers in COPD (ABC) study will determine whether the effects of inhaled corticosteroidsalone or in combination with a long-acting β2-adrenoceptor agonist reduce systemic inflammationand improve health status in patients with chronic obstructive pulmonary disease.Methods/Design: After a 4-week run-in phase during which patients with stable chronicobstructive pulmonary disease will receive inhaled fluticasone (500 micrograms twice daily),followed by a 4-week withdrawal phase during which all inhaled corticosteroids and long acting β2-adrenoceptor agonists will be discontinued, patients will be randomized to receive fluticasone (500micrograms twice daily), fluticasone/salmeterol combination (500/50 micrograms twice daily), orPublished: 06 February 2006BMC Pulmonary Medicine 2006, 6:3 doi:10.1186/1471-2466-6-3Received: 25 November 2005Accepted: 06 February 2006This article is available from: http://www.biomedcentral.com/1471-2466/6/3© 2006 Sin et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 8(page number not for citation purposes)placebo for four weeks. The study will recruit 250 patients across 11 centers in western Canada.Patients must be 40 years of age or older with at least 10 pack-year smoking history and haveBMC Pulmonary Medicine 2006, 6:3 http://www.biomedcentral.com/1471-2466/6/3chronic obstructive pulmonary disease defined as forced expiratory volume in one second to vitalcapacity ratio of 0.70 or less and forced expiratory volume in one second that is 80% of predictedor less. Patients will be excluded if they have any known chronic systemic infections, inflammatoryconditions, history of previous solid organ transplantation, myocardial infarction, orcerebrovascular accident within the past 3 months prior to study enrolment. The primary end-point is serum C-reactive protein level. Secondary end-points include circulating inflammatorycytokines such as interleukin-6 and interleukin-8 as well as health-related quality of life and lungfunction.Discussion: If inhaled corticosteroids by themselves or in combination with a long-acting β2-adrenoceptor agonist could repress systemic inflammation, they might greatly improve clinicalprognosis by reducing various complications in chronic obstructive pulmonary disease.BackgroundChronic obstructive pulmonary disease (COPD) repre-sents an increasing burden worldwide and is reported tobe the sixth leading cause of death in 1990 [1] and thefourth in 2000 [2]. Discouragingly, by the year 2020, itsmortality rate will rank third, only behind stroke andheart disease [1]. Although these figures are alarming,they are likely to be gross underestimates of the truehealth and economic burdens of COPD because COPD isan important risk factor for other causes of morbidity andmortality, including cardiovascular disorders and cancer[3,4].While the pathobiology of COPD has not been fully elu-cidated, there is a growing recognition that systemicinflammation may play a salient role in COPD progres-sion and morbidity [5]. There is now a large body of datathat show systemic inflammation exists in stable COPDand that the intensity of the inflammatory process relatesto the severity of the underlying disease [6]. Systemicinflammation has been linked with the extra-pulmonarymanifestations in COPD including sudden deaths,arrhythmias, strokes, myocardial infarction, and cancerindependent of confounding factors such as age andsmoking [4,6,7]. Additionally, in COPD, systemic inflam-mation has been associated with diminished peripheralmuscle strength, reduced exercise endurance, workload,and six-minute walk distance, poor health status, andquality of life [8]. These data suggest that systemic inflam-mation may be intrinsically involved in the downwardspiral in the health status of COPD patients. These dataalso raise the possibility that treatments modulating sys-temic inflammation could improve important health out-comes in COPD.Inhaled corticosteroids are powerful but non-specific anti-inflammatory agents commonly used to treat patientswith COPD [9]. Recent studies indicate that althoughinhaled corticosteroids do not alter the rate of decline inof decline in the patient's health status [10,11]. A pooledanalysis of clinical trial data indicates they reduce mortal-ity by ~25% relative to placebo over three to four years offollow-up [12]. Interestingly, most of the beneficial signalassociated with inhaled corticosteroids was observed in asubgroup of COPD patients with moderate to severe dis-ease [12]. In patients with mild disease, there was no sur-vival advantage. These findings are consistent with dataon exacerbations, which also demonstrate significantreductions related to inhaled corticosteroids only in thosewith moderate to severe disease [13]. Intriguingly,biomarkers of lung and systemic inflammation areincreased in COPD patients with moderate to severe dis-ease; patients with mild disease generally do not haveincreased levels of inflammatory biomarkers [14].Systemic corticosteroids reduce serum C-reactive protein(CRP) and other circulating inflammatory cytokine levelsin COPD [15]. They also down regulate certain inflamma-tory cells and cytokine levels in the airways of COPDpatients [16]. Whether inhaled steroids can reduce circu-lating CRP levels in stable COPD is less certain. A pilotrandomized clinical trial of 41 patients with COPD indi-cated that withdrawal of inhaled corticosteroids increasedserum CRP levels by ~70%; whereas a two week treatmentwith inhaled fluticasone reduced CRP levels by ~50%[15]. These findings are consistent with a recently pub-lished observational study by Pinto-Plata and colleagues,who found that users of inhaled corticosteroids hadserum CRP levels that were on average ~40% lower thanthose among corticosteroid non-users [17].Recent experimental evidence indicates that long-actingβ2-adrenoceptor agonists on their own can promote trans-location of the glucocorticoid receptor complexes fromthe cytosol to the nucleus, a process that is critical ineffecting the anti-inflammatory effects of corticosteroids[18]. When long-acting β2-adrenoceptor agonists areadded to corticosteroids, the rate of glucocorticoid recep-Page 2 of 8(page number not for citation purposes)lung function, they reduce bronchial hyperreactivity,decrease the frequency of exacerbations, and slow the ratetor translocation may be accelerated [19]. Moreover, Zhuand colleagues showed in a randomized controlled trial ofBMC Pulmonary Medicine 2006, 6:3 http://www.biomedcentral.com/1471-2466/6/3140 patients with moderate to severe COPD, that 12weeks of treatment with salmeterol plus fluticasonedecreased tissue expression of tumor necrosis factor(TNF)-α and interferon (IFN)-γ in the larger airways. Theyalso found that combination therapy decreased sputumeosinophil (p = 0.03) and subepithelial mast cell counts(p = 0.08) in the bronchial tissues [20,21]. Importantly,these cellular changes were accompanied by a reductionin the rate of exacerbations in the combination therapyarm of the study. These results demonstrate that combina-tion therapy decreases local inflammation in the lung, butwhether combination therapy reduces systemic inflam-mation is still unknown.Aims of the studyers in Western Canada is to determine whether inhaledcorticosteroids alone or in combination with a long actingβ2-adrenoceptor agonist reduce systemic inflammation instable COPD.Specific objectivesThis study will determine whether: 1) fluticasone alone orin combination with salmeterol lowers CRP levels by atleast 30% below that achieved by placebo; and 2) combi-nation therapy is better than fluticasone alone in reducingCRP levels. We will also determine whether: 1) CRP reduc-tions are associated with improved health-related qualityof life; 2) CRP reductions are associated with improvedforced expiratory volume in one second (FEV1), and 3)inhaled fluticasone alone or in combination with salme-Summary of the Trial ProtocolFigure 1Summary of the Trial Protocol. * Post bronchodilator values; all else will be pre-bronchodilator values. † Must be done prior to initiation of therapy and completion of therapy or during periods of acute exacerbation or infection. For those exacerbations or infections requiring oral steroids and/or antibiotics, patients will be asked to return 2 weeks after completing their acute exacerbation or infection treatment.Phases Run-In Withdrawal Active Treatment Weeks 1 2 3 4 5 6 7 8 9 10 11 12Placebo Advair®  500 ug bid Drugs Flovent® 500ug bid Withdrawal of Flovent®Flovent®  500 ug bid Method of Allocation of Drugs All study patients (no blinding) All study patients (no blinding) Random allocation (Participants blinded to allocation) Venipuncture for blood analysis†♥    ♥    ♥   ♥Spirometry ♥*    ♥    ♥   ♥SGRQ ♥    ♥    ♥   ♥Physical Examination ♥            Page 3 of 8(page number not for citation purposes)The primary aim of this randomized, placebo-controlled,double-blind, multi-center clinical trial involving 11 cent-terol can also reduce interleukin (IL)-6 and other pro-inflammatory biomarkers in COPD.BMC Pulmonary Medicine 2006, 6:3 http://www.biomedcentral.com/1471-2466/6/3Methods/designOverview of the study designThis trial is a double blind study comparing the effects ofinhaled fluticasone alone or in combination with salme-terol against placebo on serum CRP levels in COPD. Allstudy participants will first undergo a run-in phase duringwhich they will be treated with fluticasone 500 mcg bidfor 4 weeks. This will be followed by a withdrawal phasewherein all participants will be free of any inhaled corti-costeroids or theophylline products for 4 weeks. After thewithdrawal phase, participants will be randomly assignedto one of three arms: placebo; inhaled fluticasone (500mcg bid); or inhaled fluticasone/salmeterol combinationfied according to current smoking status with allocationconcealment in a 1 (placebo arm) to 2 (fluticasone arm)to 2 (combination arm) distribution ratio. In this phase,all participants and study personnel will be blinded to thetreatment assignment. This phase will last for 4 weeks. Forsafety reasons, during severe exacerbations (i.e. thoserequiring hospitalization or emergency visit for COPD),the treating physician can break the "code" and placestudy participants on medications needed to treat theexacerbation (See Figure 1 for protocol summary)Details of the run-in phase (4 weeks)During this phase, all pulmonary medications with signif-Management of Exacerbations during the StudyFigur  2Management of Exacerbations during the Study. Abbreviations: LABA, long-acting β2 adrenoceptor agonist; SGRQ, St. George's Respiratory Questionnaire.Run-In Period                Patient Taking fluticasoneWash Out Period            No steroids or LABATreatment Period           Patient Taking Randomization DrugRestart Treatment PhaseIf Exacerbation or InfectionContinue with regular medications for 2 weeks post-treatment of exacerbation or infection Exacerbation/Infection Flow SheetBlood drawn if possible during Exacerbation/InfectionIf Exacerbation or InfectionBlood drawn if possible during Exacerbation/InfectionReturn to week 1(visit)Restart Run-In PhaseContinue with regular medications for 2 weeks post-treatment of exacerbation or infection Exacerbation TreatmentExacerbation TreatmentIf Exacerbation or InfectionBlood drawn if possible during Exacerbation/InfectionRestart Run-In PhaseContinue with regular medications for 2 weeks post-treatment of exacerbation or infection Exacerbation TreatmentReturn to Week 7Return to week 1(visitDiscontinue Study TreatmentPage 4 of 8(page number not for citation purposes)(500/50 mcg bid). Randomization will be carried out cen-trally according to a computer-generated sequence strati-icant anti-inflammatory effects (e.g. inhaled corticoster-oids, theophyllines, and leukotriene modifiers) will beBMC Pulmonary Medicine 2006, 6:3 http://www.biomedcentral.com/1471-2466/6/3discontinued. All participants will be maintained oninhaled fluticasone (500 mcg bid; Flovent Diskus®, Glax-oSmithKline Canada, Mississauga, ON). Short-acting β2-adrenoceptor agonists (e.g. salbutamol) and/or anti-cholinergic (ipratropium) will be allowed as rescue medi-cations. Long-acting anticholinergic medication (i.e.tiotropium) will also be permitted, if clinically indicatedas judged by the participants' attending physician. Long-acting β2-adrenoceptor agonists, however, will be prohib-ited.Details of the withdrawal phase (4 weeks)During this phase, inhaled fluticasone will be discontin-ued and participants will not be allowed to take any otherinhaled corticosteroids, theophyllines or leukotrienemodifiers. Short-acting β2-adrenoceptor agonists (e.g.salbutamol) and/or anti-cholinergic (ipratropium) inhal-ers will be allowed as rescue medications. Long-actinganticholinergic inhaler (i.e. tiotropium) will be permittedas maintenance medication. Long-acting β2-adrenoceptoragonists will be prohibited.Details of the active treatment phase (4 weeks)All participants will be randomized to one of 3 arms of thetrial: placebo (placebo diskus, GlaxoSmithKline Canada,Mississauga, ON), inhaled fluticasone (500 mcg bid; Flov-ent Diskus®, GlaxoSmithKline Canada, Mississauga, ON)or inhaled fluticasone/salmeterol (500/50 mcg bid;Advair Diskus® GlaxoSmithKline Canada, Mississauga,ON). Short-acting β2-adrenoceptor agonists (e.g. salbuta-mol) and/or anti-cholinergic inhaler (ipratropium) willbe allowed as rescue medications. Long-acting anticholin-ergic medication (i.e. tiotropium) will be allowed asmaintenance medication if clinically indicated as judgedby the participants' attending physician. Any other long-acting β2-adrenoceptor agonists or inhaled corticosteroidswill not be allowed. As well, theophyllines or leukotrienemodifiers will not be permitted in this phase.Exacerbations during the study period (see figure 2)The participants will be instructed at enrollment to con-tact the local study coordinator at the earliest opportunityif their usual COPD symptoms (i.e. cough, dyspnea, spu-tum production, or sputum color change) worsen, or ifthey develop a fever (of unknown source), or active infec-tions elsewhere (e.g. sinusitis). During exacerbations,study coordinators will see the participants as soon as pos-sible and will codify all exacerbations according to Pag-giaro's criteria [22]. A mild episode is one that can be self-managed by the patient at home, requiring only intensifi-cation of current therapy; a moderate event is defined asrequiring antimicrobial and/or oral corticosteroid ther-apy; and severe is defined as an event requiring admission(principal) investigators using the Canadian ThoracicSociety guidelines in consultation with the participants'primary care provider [23]. Blood samples will beobtained at the time of the exacerbation. If participants donot or can not contact study coordinators during severeexacerbations, the study coordinator will make everyattempt to obtain blood samples from the patients at thetime of their presentation to the emergency department orhospital. For those who experience an exacerbationrequiring systemic corticosteroids and/or antimicrobials,the study patients will be asked to return 2 weeks afterthey finish their course of exacerbation medications atwhich point their blood, spirometry, and health statusmeasurements will be collected. Once clinical stability isachieved for a minimal of 2 weeks, the participants willresume study participation in accordance to the schedulepublished in figure 2.Study participantsAll participants must have a clinical diagnosis of COPD asdefined by the Global Initiative for Chronic ObstructiveLung Disease (GOLD) guidelines [24]. Spirometric crite-ria will include a FEV1 of less than 80% of predicted withan FEV1 to forced vital capacity (FVC) ratio of less than0.70 (post-bronchodilator values). Additional inclusioncriteria will be a cigarette smoking history of more than 10pack-years, clinical stability as defined by the absence ofexacerbations for at least 4 weeks, and age ≥ 40 years.Exclusion criteria will be any known disseminated malig-nancy, known chronic systemic infections or inflamma-tory conditions (e.g. rheumatoid arthritis, systemic lupuserythematosis, active sarcoidosis), previous solid organtransplantation, myocardial infarction or cerebrovascularaccident within the past 3 months prior to study enrol-ment, females of child-bearing age (i.e. must be amenor-rheic for at least 12 months), participation in a drug trialwithin the past 4 weeks prior to study enrolment, any sub-ject who is unlikely to survive more than 6 months, recentupper respiratory tract infection within the 4 weeks priorto enrolment, unable to follow instructions, patients onchronic oral theophyllines and unable or unwilling tocome off theophyllines for the study period, oral corticos-teroids, or long-term immunosuppressive agents.Laboratory & other measurementsBlood collectionDuring every visit (and in the case of an exacerbation and/or infection according to Figure 2), study personnel willtake two 10 ml collection of blood from participantsthrough venipuncture using standard techniques. Onesample (~10 mls) will be collected in tubes that do notcontain an anti-coagulant and another in a tube that doescontain an anti-coagulant. The tubes without the anti-Page 5 of 8(page number not for citation purposes)to a hospital or an emergency department. Treatmentdecisions during exacerbations will be rendered by the sitecoagulant will be allowed to clot for at least 30 minutes,then centrifuged at ≥ 1500 × g for 15 min at room temper-BMC Pulmonary Medicine 2006, 6:3 http://www.biomedcentral.com/1471-2466/6/3ature and then divided into aliquots (at least 2 serum sam-ples) using a sterile plastic transfer pipet. The serumaliquots will be placed into supplied microtubes contain-ing an anti-protease. Until used, the tubes containing theanti-protease will be stored in a -20°C freezer. The serumsamples mixed with the anti-protease will be temporarilystored in a portable cooler containing frozen gel-packsand refrigerated at 4°C. Same-day shipment of the serumsamples will be organized by the participating site to thecentral core laboratory located James Hogg iCAPTURECentre for Cardiovascular and Pulmonary Research, St.Paul's Hospital, Vancouver, British Columbia, using acourier service, guaranteeing arrival within 24 hours ofshipment. The tube with the anticoagulant will be tempo-rarily stored in a portable cooler containing frozen gel-packs and refrigerated (4°C) until same day shipment tothe central coordinating centre's laboratory in Vancouveroccurs. From these samples, the participants' serum C-reactive protein (CRP) levels will be determined using acommercially available high-sensitivity enzyme-linkedimmunosorbent assay (ELISA) kits (Alpha Diagnostics,San Antonion, Tx). Serum concentrations of IL-6, TNF-α,and other inflammatory mediators will also be measuredusing commercially available ELISA kits.SpirometrySpirometry will be performed for each participant at eachvisit in accordance with the guidelines from the AmericanThoracic Society [25]. A test session will consist of severalrepeated FVC maneuvers. Each maneuver will require thesubject to take the deepest possible breath and exhale intoa spirometer as hard, fast, and completely as possible. Thespirometer will record the volume of air exhaled as a func-tion of time. Each subject will perform at least three FVCmaneuvers. For a maneuver to be acceptable, it needs tobe a maximal exhalation free from cough, excessive hesi-tation, leak, obstructed mouthpiece, variable effort, orearly termination. At the first visit, pre and post-bron-chodilator measurements will be done. For follow-up vis-its, only pre-bronchodilator values will be measured.Health status measurementsDuring each visit, a disease-specific health measure, St.George's Respiratory Questionnaire (SGRQ), will beadministered by the study co-ordinator at each site [26].The scores for each section including symptom score (fre-quency and severity), activity score (activities that cause orare limited by breathlessness), and impact score (socialfunctioning, psychological disturbances resulting fromairways disease), as well as a total score will be calculatedusing established methods [26].OutcomesPrimary endpointThe primary endpoint of the study is serum CRP level. Weanticipate that inhaled fluticasone alone or in combina-tion with salmeterol will reduce CRP levels by at least 30%below that achieved by placebo. We will also determinewhether combination therapy reduces CRP levels beyondthat achieved by fluticasone mono-therapy.Secondary endpointsThe secondary endpoints will include: 1) changes in otherinflammatory mediators such as IL-6, TNF-α, and mono-cyte chemotactic protein (MCP-1); 2) changes in SGRQscores; 3) changes in FEV1; and 4) rates of exacerbationsStatisticsMain analysisFor the primary analysis, we will compare the changes inCRP at 4 weeks from baseline between those assigned toinhaled fluticasone alone or in combination with salme-terol and those assigned to placebo based on an intention-to-treat principle. We will use between group t-tests todetermine whether the changes in CRP between thegroups are statistically significant and a mixed effectsmodel to adjust for any significant differences in the base-line characteristics of the study participants across thegroups.Secondary analysesWe will perform similar analysis on TNF-α, IL-6 and MCP-1 (as well as other important inflammatory molecules).We will use Pearson's correlation techniques (as well asadjusted linear regression) to determine whether changesin CRP levels correlate with changes in SGRQ scores. Pre-vious studies indicate that SGRQ improves with flutica-sone with or without salmeterol, independent of theireffects on FEV1 [10]. We hypothesize that SGRQ may cor-relate with CRP.Sample size calculationWe will enroll 250 participants with COPD for this study.This will permit 100 participants to be assigned to flutica-sone and combination treatment groups, respectively, and50 participants will be exposed to a placebo during theactive treatment phase. We have calculated our samplesize based on the following assumptions: 1) we anticipatethat fluticasone relative to placebo will lower baselineCRP levels by ~1.5 mg/L with standard deviation of 3.5mg/L; 2) we will perform between group comparison ofCRP (from baseline) using independent two sample t-testat alpha of 0.05 (two-tailed) and a power of ≥80%.Ethical considerationsPage 6 of 8(page number not for citation purposes)The protocol and procedures as described above havereceived institutional approval from the University of Brit-BMC Pulmonary Medicine 2006, 6:3 http://www.biomedcentral.com/1471-2466/6/3ish Columbia/Providence Research Ethics Board, as wellas from all local institutional ethics review board of eachparticipating site. The funding for the study is from Glax-oSmithKline (Mississauga, ON). The funding source hasno role in the design, conduct, analysis, interpretation, orreporting of the study and will not have access to the rawdata. All data will be housed at the James Hogg iCAPTURECenter in Vancouver, BC.DiscussionIn this paper, we have reported the background, therationale, and the study protocol for a unique multi-center randomized controlled trial whose main outcomeis a biochemical measurement (i.e. CRP). The study willtest the hypothesis that inhaled corticosteroids alone or incombination with a long-acting β2-adrenoceptor agonistwill reduce CRP levels in stable COPD patients. To ourknowledge, this is the first clinical trial in COPD whosemain outcome is serum CRP. Additionally, this study willbe able to determine the effects of these medications onother relevant inflammatory biomarkers and likely pro-vide a solid biological rationale for the clinical effects ofinhaled corticosteroids and combination therapy inCOPD.There are certain limitations of this trial. Firstly, the studywill not measure any parameters of inflammation in thelung. We decided against collecting biological samplesfrom the airways because: 1) a recently conducted andpublished randomized controlled trial demonstrated thatcombination therapy reduces airway inflammation[20,21]; 2) there remains considerable amount of contro-versy regarding the utility of exhaled condensates andinduced sputum in assessing airway inflammation inCOPD [28]; 3) more invasive measurements (e.g. bron-choscopy) would have significantly reduced the projectedrecruitment rate of participants, reducing the power of thestudy to detect relevant differences in CRP; and 4) the pri-mary focus of this study was to assess the effects of combi-nation and steroid therapy on systemic inflammation.Secondly, the study has a relatively short follow-upperiod. We decided against a longer period of follow-upfor pragmatic reasons. In our previous pilot study, weobserved significant changes in CRP with inhaled corti-costeroids after only 2 weeks of treatment [15]. Addition-ally, we were concerned that follow-up longer than fourweeks would be associated with increased drop-out rates,and exacerbations, reduced compliance with the studymedications, and changes in medications (both pulmo-nary and nonpulmonary drugs) that may alter CRP levels.Thirdly, we cannot be certain that changes in CRP levelswill necessarily result in significant changes in health out-comes of COPD patients, though there is a body of indi-work is needed in future studies to establish a causal linkbetween CRP and health outcomes in COPD.In summary, the present study will determine whetherinhaled fluticasone alone or in combination with salme-terol has any significant systemic anti-inflammatoryeffects. Since systemic inflammation has been linked witha variety of important complications in COPD includingperipheral muscle dysfunction, cachexia, cardiovascularcomplications and cancer, if these medications do indeedreduce systemic inflammation, this will provide an impor-tant biological mechanism by which they improve healthoutcomes in COPD. Additionally, this study will serve asan important template for future studies, linking systemicinflammation with clinical outcomes in COPD.AbbreviationsCOPD = chronic obstructive pulmonary diseaseCRP = C-reactive proteinTNF = tumor necrosis factorIFN = interferonIL = interleukinFEV1 = forced expiratory volume in one secondFVC = forced vital capacitySGRQ = Saint George's Respiratory QuestionnaireMCP-1 = monocyte chemoattractant protein-1ELISA = enzyme-linked immunosorbent assayON = OntarioCompeting interestsDDS & SFP have received honoraria for speaking engage-ments and research funding from GlaxoSmithKline(GSK).Authors' contributionsAll of the authors contributed to the manuscript and tothe project. DDS & SFP conceived the study, wrote the ini-tial protocol, and obtained funding.AcknowledgementsThe ABC trial is funded by GlaxoSmithKline. The funding source had no role in the study conception or design. All data analyses will be conducted independently of the funding source at the James Hogg iCAPTURE Center (St. Paul's Hospital, Vancouver, BC.). The primary data will be held at the Page 7 of 8(page number not for citation purposes)rect evidence suggesting that they do [6,14,17]. AdditionalJames Hogg iCAPTURE Center. The funding source will not be involved in the analysis or interpretation of the data.BMC Pulmonary Medicine 2006, 6:3 http://www.biomedcentral.com/1471-2466/6/3DDS is a holder of a Canada Research Chair (COPD) and a GlaxoSmithK-line/St. Paul's Foundation Professorship in COPD.MF is supported by the Michael Smith Distinguished Scholar Award and the BC Lung CIHR Scientist Award.The authors wish to acknowledge and thank the site co-ordinators: Janet Baron (Royal University Hospital, Saskatoon), Georgina Lopez (St. Paul's Hospital, Vancouver), Anju Mainra (Lion's Gate Hospital, North Vancou-ver), Linda Hui, Maureen Sigurdson (Vancouver General Hospital, Vancou-ver), Kathy Duce (Lethbridge Regional Hospital, Lethbridge), Jill Edwards, Angie Depner (Links Clinic, Edmonton), Jennifer Barchard, (Grey Nuns Community Hospital, Edmonton), Heidi Haupt (University of Alberta, Edmonton), Teena Rossitter (Wetaskiwin Lung Laboratory, Wetaskiwin), Amin Thawer, Diane Conley, Gladys Wolters (University of Calgary, Cal-gary).The authors also wish to thank Mrs. Claire Gray (laboratory manager), Dr. Wen Qi Gan (Data Analyst), Dr. Ted Watson (GSK) and Ms. Jill Waddell (GSK) for their contributions to the project.References1. 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