Can Advair and Flovent Reduce Systemic Inflammation Related to Chronic Obstructive Pulmonary Disease (COPD)? A Multi-Center Randomized Controlled Trial
Can Advair and Flovent Reduce Systemic Inflammation Related to Chronic Obstructive Pulmonary Disease (COPD)? A Multi-Center Randomized Controlled Trial
Large population-based studies suggest that patients with chronic obstructive pulmonary
 disease (COPD) are 2 to 3 times at risk for cardiovascular mortality, which accounts for a
 large proportion of the total number of deaths. How COPD increases the risk of poor
 cardiovascular outcomes is largely unknown. However, there is growing evidence that
 persistent low-grade systemic inflammation is present in COPD and that this may contribute to
 the pathogenesis of atherosclerosis and cardiovascular disease among COPD patients.
 Inflammation and more specifically, C-reactive protein (CRP), has been linked with all stages
 of atherosclerosis, including plaque genesis, rupture and subsequent thrombo-fibrosis of
 vulnerable vessels. Recently, our group has demonstrated in a relatively small study that
 short-term inhaled corticosteroid (ICS) therapy can repress serum CRP levels in stable COPD
 patients. Conversely, withdrawal of ICS leads to a marked increase in serum CRP levels.
 Although very promising, these data cannot be considered definitive because the study was
 small in size and scope (N=41 patients). Additionally, this study did not address the
 potential effects of combination therapy with ICS and long-acting β2 agonists (LABA). This is
 an important short-coming because combination therapy of ICS and LABA have been shown to
 produce improved clinical outcomes over ICS monotherapy and is commonly used by clinicians in
 the treatment of moderate to severe COPD. We hypothesize that inhaled fluticasone (Flovent®)
 reduces systemic inflammation and that combination therapy (Advair®) is more effective than
 steroids alone in reducing systemic inflammation in COPD. In this proposal, we will implement
 a randomized controlled trial to determine whether ICS by themselves or in combination with
 LABAs can:

 1. reduce CRP levels in stable COPD patients and

 2. reduce other pro-inflammatory cytokines, which have been linked with cardiovascular
 morbidity and mortality such as interleukin-6 (IL-6) and monocyte chemoattractant
 protein-1 (MCP-1)
What is the problem to be addressed? Patients with chronic obstructive pulmonary disease
 (COPD) are at increased risk of cardiovascular events. Indeed, ischemic heart disease is one
 of the leading causes of mortality and hospitalization among patients with mild to moderate
 COPD. For every 10% decrease in forced expiratory volume in one second (FEV1), cardiovascular
 mortality increases by ~28%, and nonfatal coronary event increases by ~20% in mild to
 moderate COPD. How COPD increases the risk of poor cardiovascular outcomes is largely
 unknown. However, there is growing evidence that persistent low-grade systemic inflammation
 is present in COPD and that this may contribute to the pathogenesis of atherosclerosis and
 cardiovascular disease among COPD patients. Circulating levels of C-reactive protein (CRP),
 which has been strongly linked with poor cardiovascular outcomes in the general population,
 has been demonstrated to be elevated in COPD. Moreover, an elevated level of CRP has been
 associated with myocardial injury in COPD. Reduction in the level of CRP, on the other hand,
 has been shown to be associated with improved outcomes in various populations. Other
 cytokines such as interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), which
 are potent regulators of CRP, have also been associated with cardiovascular events. If this
 linkage between systemic inflammation and atherosclerosis holds true for COPD, then systemic
 inflammation and/or its markers may provide a new and very important therapeutic target for
 COPD management. Corticosteroids (CS) can reduce CRP and other circulating inflammatory
 cytokine levels in acute pro-inflammatory states. They can also down-regulate certain
 inflammatory cells and cytokine expression in the airways of COPD patients and attenuate
 airway hyperresponsiveness related to COPD. More importantly, in large clinical studies, they
 have been shown to reduce clinical exacerbations, improve health status and may even reduce
 mortality in COPD. The mechanism by which such improvement occurs is not known. Recently, our
 group has demonstrated in a relatively small study that short-term inhaled corticosteroid
 (ICS) therapy can repress serum CRP levels in stable COPD patients. Conversely, withdrawal of
 ICS leads to a marked increase in serum CRP levels. Although very promising, these data
 cannot be considered definitive because the study was small in size and scope (N=41
 patients). Additionally, this study did not address the potential effects of combination
 therapy with ICS and long-acting β2 agonists (LABA).This is an important short-coming because
 combination therapy has been shown to produce improved clinical outcomes over ICS monotherapy
 and is commonly used by clinicians in the treatment of moderate to severe COPD. In-vitro
 studies suggest that steroids and LABAs may "synergistically" down-regulate inflammation in
 COPD. Whether this occurs in-vivo remains largely unknown and untested.

 What is the proposed trial design:

 This trial will be a double blind, placebo-controlled multi-center study comparing the
 effects of Advair, Flovent and placebo on serum CRP in COPD. All study participants will
 first undergo a run-in phase during which all will be treated with Flovent 500 mcg bid. This
 will be followed by a withdrawal phase wherein all participants will be FREE of any ICS or
 LABAs for 4 weeks. After the withdrawal phase, the participants will be randomly assigned
 (using a computer generated algorithm) to one of three arms: placebo; Flovent; or Advair
 Run-In Phase (4 weeks): The use of ICS, theophyllines, and leukotriene modifiers, LABA will
 be prohibited and subjects will be maintained on Flovent 500 mcg bid. Regular use of
 tiotropium and as needed use of short-acting β2 (salbutamol) and/or anti-cholinergic
 (Atrovent) will be allowed.

 Why is this phase needed? Management of COPD is variable. Because of the controversy
 surrounding the use of ICS and LABAs, some patients at enrollment will be taking these
 medications, while others will not. This phase is to ensure uniformity of therapy (and in
 particular to the use of ICS in the same dose) for all study participants.

 Withdrawal Phase (4 weeks): Flovent will be discontinued and participants will also not be
 taking any other ICS, theophyllines, LABAs or leukotriene modifiers during this period.
 Regular use of tiotropium and as needed use of short-acting β2 (salbutamol) and/or
 anti-cholinergic (Atrovent) will be allowed.

 Why is this phase needed? There are two principal reasons why this phase is needed. One way
 of "proving" that ICS modifies serum CRP levels is to demonstrate that withdrawal of ICS
 increases CRP levels and their re-introduction of ICS suppresses CRP levels. The Second
 reason is that in the researchers' pilot study it was found that serum CRP levels were
 highest when patients were off ICS for 4 weeks. To achieve the necessary statistical power
 for this study, a reasonably high serum CRP signal is desirable at the beginning of the
 randomization period.

 Active Treatment Phase (4 weeks): Subjects will be randomized to one of 3 arms, placebo,
 Advair, or Flovent. Rescue medications (anti-cholinergics and short-acting β2) will be
 allowed. Participants will not be taking any other inhaled corticosteroids, theophyllines,
 leukotriene modifiers or LABAs during this period.

 Why is this phase only 4 weeks? Exacerbations and infections can elevate CRP levels by 2 to
 10 fold. The rate of normalization of CRP levels after these episodes is variable; complete
 normalization may not take place for several weeks after the resolution of the infective or
 exacerbation episode. To reduce the risk that the study participants will experience
 clinically apparent infections or exacerbations, we have made this phase of the study
 relatively short (4 weeks). The short treatment period will also reduce the effects of non or
 suboptimal compliance of treatment medications on CRP levels. We believe that 4 weeks of
 therapy will be sufficient to demonstrate the suppressive effects of Flovent and Advair,
 given the fact that in the pilot study, an effect of Flovent on CRP after only 2 weeks of
 therapy was observed.

 What are the proposed practical arrangements for allocating participants to trial groups?
 Patients will be randomized (1:2:2) to placebo, Advair, or Flovent. Patients will first be
 stratified based on study site to minimize the potential impact of variation in patient care
 across the study sites on the endpoint of interest. We have hired an external statistician
 (Ms. Lieling Wu) who will prepare computer-generated randomization lists blocked by study
 site using permuted blocks of six. The lists will be inputted into a randomization computer.
 When a site coordinator has identified an eligible, consented patient, he/she will contact
 the central co-ordinating site at St. Paul's Hospital (SPH) for a randomization number. The
 randomization computer will then issue a study identification number to the study coordinator
 and to GlaxoSmithKline (Mississauga) for delivery of the appropriate treatment package (that
 contains one Flovent canister and one "unknown" puffer) to the appropriate study site within
 two business days. The open-labeled Flovent will be used for the "run-in" phase, while the
 "unknown" puffer (either placebo, Flovent or Advair) will be dispensed at the start of the
 "active treatment phase."

 What are the proposed methods for protecting against other sources of bias ? All research
 personnel will all be blinded to the treatment group except for the study biostatistician,
 who will be responsible for the randomization computer. Only he will have access to the
 master file, which can link patient identifiers to the randomization number. This computer
 will be locked away in a secure space at the James Hogg iCAPTURE Centre in SPH and will have
 a password protection that only he (or his designate) can access. The study medications and
 placebo will be packaged and delivered identically as a diskus.

 What is the proposed duration of treatment period? 4 weeks of run-in; 4 weeks of withdrawal
 phase and 4 weeks of active treatment phase (i.e RCT).

 What is the frequency and duration of followup? Participants will be seen at enrollment,
 after the completion of each phase of the study and with exacerbations or infections (as
 defined above).

 What are the proposed primary and secondary outcome measures?

 Primary: The difference in CRP from start of the active treatment phase to the end of the
 trial between the 3 groups

 Secondary: measurements of MCP-1 and IL-6; St. George's Respiratory Questionnaire, SGRQ,76
 scores; FEV1

 How will the outcome measures be measured at follow-up?

 Blood Collection: During every visit, study personnel will take two 10 ml collection of blood
 from participants through venipuncture (using standard techniques). Samples will be
 centrifuged and the serum component will be aliquoted into special tubes (provided by the
 coordinating site) that contain anti-proteases. They will then be shipped (Fedexed) in
 regular ice immediately to the Study Coordinating Center (to arrive within 24 hours of blood
 collection) where they will be frozen in liquid nitrogen and stored in -70ºC freezers until
 analysis. To avoid delays, no samples will be taken on a Friday or a day preceding holidays.
 A high-sensitive solid phase enzyme-linked immunosorbent assay (ELISA) to measure serum CRP
 will be used. The investigators have measured over 4,000 serum samples from the Lung Health
 Study with this technique. In comparison with nephelometry, another commonly used technique,
 CRP levels with high-sensitivity ELISA is excellent. The coefficient of variation for CRP in
 the researchers' laboratory is ~5%. IL-6 and MCP-1 will also be measured using
 high-sensitivity ELISA assays. The researchers' laboratory has also experience performing
 these assays using serums collected from COPD patients. The investigators have previously
 shown that the coefficient of variation for the IL-6 assay to be 4.7% (median; interquartile
 range, 1.8% to 11.2%) and the MCP-1 assay to be 3.2% (median; interquartile range, 1.5% to
 5.9%).

 Spirometry: Spirometry will be performed in accordance with guidelines from the American
 Thoracic Society during each visit. At the first visit, pre and post-bronchodilator
 measurements will be done. For follow-up visits, only pre-bronchodilator values will be
 measured.

 Health Status Measurements: During each visit, study participants will complete the SGRQ in
 person. The SGRQ was chosen because it has excellent internal consistency (Cronbach's alpha
 coefficient ≥ 0.76), reliability (intraclass correlation coefficient of ~85% of responses
 measured 6 months apart), and is an independent predictor of future risk of exacerbations and
 mortality in COPD. Clinically relevant thresholds for SGRQ are considered to be score changes
 of ≥ 4.0 units.

 What is the proposed sample size? In the pilot study (described above), it was found that
 after 2 weeks, compared with the placebo group, those assigned to fluticasone experienced a
 significant decrease in CRP levels from baseline, after adjustments for baseline FEV1, age,
 and sex of participating patients (57.1% decrease relative to placebo; p=0.042). The
 (geometric) mean of CRP for this cohort was 4.9 mg/L (95% CI, 3.3 to 7.1). Sample sizes of
 200 participants combined in Flovent and Advair group (100 in each) and 50 in the placebo
 group will be needed.
Inclusion Criteria:

 -  All patients must have a clinical diagnosis of chronic obstructive pulmonary disease
 according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines.

 -  Patients must have a cigarette smoking history of more than 10 pack-years

 -  Patients must be clinically stable and at least 4 weeks from last acute exacerbation
 (and return to baseline level of symptoms)

 -  Patients must have an FEV1 of less than 80% of predicted values with FEV1 to FVC ratio
 of less than 0.70 (post-bronchodilator values)

 -  Men or women ≥ 45 years of age