Can Advair and Flovent Reduce Systemic Inflammation Related to Chronic Obstructive Pulmonary Disease (COPD)? A Multi-Center Randomized Controlled Trial
Information source: University of British Columbia
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Chronic Obstructive Pulmonary Disease
Intervention: Advair (Drug); Flovent (Drug)
Phase: Phase 4
Status: Recruiting
Sponsored by: University of British Columbia Official(s) and/or principal investigator(s): Don Sin, MD, Principal Investigator, Affiliation: University of British Columbia
Overall contact: Roxanne Rousseau, BS, Phone: 604-977-9791, Email: RRousseau@mrl.ubc.ca
Summary
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)
Clinical Details
Official title: Advair - CRP Study
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment
Primary outcome: Change in serum C-reactive protein levels over 3 months between treatment groups.
Secondary outcome: changes in serum interleukin levels; quality of life; FEV1 between treatment groups
Detailed description:
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.
Eligibility
Minimum age: 45 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
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
Locations and Contacts
Roxanne Rousseau, BS, Phone: 604-977-9791, Email: RRousseau@mrl.ubc.ca
University of Calgary, Calgary, Alberta T2V 1P9, Canada; Recruiting Gladys Wolters, BS, Phone: 403-943-3292, Email: Gladys.Wolters@CalgaryHealthRegion.ca Gordon Ford, MD, Principal Investigator Robert Cowie, MD, Principal Investigator
Grey Nuns Hospital, Edmonton, Alberta T6L 5X8, Canada; Recruiting Jennifer Barchard, BS, Phone: 780.450.7178, Email: JBarchar@cha.ab.ca Lyle Melenka, MD, Principal Investigator
Links Clinic, Edmonton, Alberta T5G 3G6, Canada; Recruiting Jill Edwards, BS, Phone: 780-913-4240, Email: jilledwards@shaw.ca Warren Ramesh, MD, Principal Investigator
University of Alberta Hospital, Edmonton, Alberta T6G 2B7, Canada; Recruiting Heidi Haupt, BS, Phone: (780) 407-7591, Email: hhaupt@ualberta.ca Eric Wong, MD, Principal Investigator
Lethbridge Regional Hospital, Lethbridge, Alberta T1J 1W5, Canada; Recruiting Kathy Duce, BS, Phone: 403-388-6031, Email: kduce@mail.chr.ab.ca Eric Wilde, MD, Principal Investigator
Wetaskiwin Lung Laboratory, Wetaskiwin, Alberta T9A 3B8, Canada; Recruiting Teena Rossiter, BS, Phone: 780.352.7085, Email: teena@incentre.net Ernest York, MD, Principal Investigator
Lion's Gate Hospital, North Vancouver, British Columbia V7L 2N3, Canada; Recruiting Anju Mainra, BS, Phone: : 604.649.5852, Email: mainra@shaw.ca Raj Mainra, MD, Principal Investigator
St. Paul' Hospital, Vancouver, British Columbia V6Z 1Y6, Canada; Recruiting Roxanne Rousseau, BS, Phone: 604-977-9791, Email: RRousseau@mrl.ubc.ca Paul Man, MD, Principal Investigator Don Sin, MD, Principal Investigator
Vancouver General Hospital, Vancouver, British Columbia V5Z 3J5, Canada; Recruiting Linda Hui, BS, Phone: 604.875.5697, Email: lindahui@interchange.ubc.ca Mark Fitzgerald, MD, Principal Investigator
Royal University Hospita, Saskatoon, Saskatchewan S7N 0W8, Canada; Recruiting Janet Baron, BS, Phone: 306.966.7871, Email: janetbaron@shaw.ca Darcy Marciniuk, MD, Principal Investigator John Reid, MD, Sub-Investigator
Additional Information
Related publications: Sin DD, Man SF, Marciniuk DD, Ford G, FitzGerald M, Wong E, York E, Mainra RR, Ramesh W, Melenka LS, Wilde E, Cowie RL, Williams D, Rousseau R; ABC (Advair, Biomarkers in COPD) Investigators. Can inhaled fluticasone alone or in combination with salmeterol reduce systemic inflammation in chronic obstructive pulmonary disease? Study protocol for a randomized controlled trial [NCT00120978]. BMC Pulm Med. 2006 Feb 6;6:3.
Starting date: December 2004
Last updated: May 8, 2006
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