Ignite Creation Date:
2024-05-05 @ 11:46 AM
Last Modification Date:
2024-10-26 @ 9:12 AM
Study NCT ID:
NCT00120978
Status:
UNKNOWN
Last Update Posted:
2006-05-09
First Post:
2005-07-11
Brief Title:
Can Advair and Flovent Reduce Systemic Inflammation Related to Chronic Obstructive Pulmonary Disease COPD A Multi-Center Randomized Controlled Trial
Sponsor:
University of British Columbia
Organization:
University of British Columbia
Study Overview
Official Title:
Advair - CRP Study
Status:
UNKNOWN
Status Verified Date:
2005-04
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 N41 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
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
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 andor 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 N41 patients Additionally this study did not address the potential effects of combination therapy with ICS and long-acting β2 agonists LABAThis 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 andor 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 andor 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 122 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 heshe will contact the central co-ordinating site at St Pauls 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 ie 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 Georges Respiratory Questionnaire SGRQ76 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 4000 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 47 median interquartile range 18 to 112 and the MCP-1 assay to be 32 median interquartile range 15 to 59
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 Cronbachs alpha coefficient 076 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 40 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 571 decrease relative to placebo p0042 The geometric mean of CRP for this cohort was 49 mgL 95 CI 33 to 71 Sample sizes of 200 participants combined in Flovent and Advair group 100 in each and 50 in the placebo group will be needed
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 andor 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 andor 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 122 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 heshe will contact the central co-ordinating site at St Pauls 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 ie 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 Georges Respiratory Questionnaire SGRQ76 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 4000 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 47 median interquartile range 18 to 112 and the MCP-1 assay to be 32 median interquartile range 15 to 59
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 Cronbachs alpha coefficient 076 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 40 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 571 decrease relative to placebo p0042 The geometric mean of CRP for this cohort was 49 mgL 95 CI 33 to 71 Sample sizes of 200 participants combined in Flovent and Advair group 100 in each and 50 in the placebo group will be needed
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| SC0100141 | None | None | None |