WEUSKOP6416: Evaluating Pneumonia in Chronic Obstructive Pulmonary Disease (COPD) Subjects
Information source: GlaxoSmithKline
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Pulmonary Disease, Chronic Obstructive
Intervention: New users of ADVAIR DISKUS, ADVAIR HFA (ICS) - containing medications (Drug); New users of FLOVENT DISKUS, FLVENT HFA (long-acting bronchodilators (LABD)) (Drug)
Phase: N/A
Status: Completed
Sponsored by: GlaxoSmithKline Official(s) and/or principal investigator(s): GSK Clinical Trials, Study Director, Affiliation: GlaxoSmithKline
Summary
Pneumonia remains an important cause of morbidity and mortality in older adults with
obstructive lung disease. Risk factors for pneumonia, including episodes associated with a
hospital admission, have been extensively characterized in clinical trials and
observational studies of patients with COPD, and include older age, lower predicted FEV1
(<50%), prior COPD exacerbations, dyspnea , normal to low body mass index (<25), current
smoking and certain co-morbid conditions (e. g. dementia). The use of inhaled
corticosteroids (ICS) has also been identified, as associated with an increased risk of
pneumonia in patients with COPD.
The primary objective of this study is to estimate the magnitude of known risk factors and
the outcomes of pneumonia requiring hospitalization and the potential effect modification of
these risk factors by ICS use. The primary endpoints will be severe pneumonia, defined as
community-acquired pneumonia (CAP) resulting in hospitalization and/or death and
hospital-acquired pneumonia (HAP) diagnosed after two days in the hospital. As a secondary
endpoint, CAP that did not result in hospitalization or death will be examined. As a
secondary objective, we will describe characteristics for those patients who develop
pneumonia requiring hospitalization compared to those with pneumonia not requiring
admission.
This study will use the General Practice Online Database (GOLD), formerly referred to as the
General Practice research Database (GPRD), a primary care electronic medical record
database.
A new user cohort will be defined among patients with COPD who are 45 years and older in the
United Kingdom. Patients will be considered a new user of ICS-containing medications if
they had not received a prescription for an ICS-containing medication in the prior year.
The comparator treatment group will be new users of long-acting bronchodilators (LABD),
including long-acting beta-agonists (LABA) or long-acting antimuscarinics (LAMA). In the
one year washout period, all new users could not have either ICS-containing medications or
LABD.
Prior to conducting the analysis, feasibility analyses will be conducted to evaluate of the
number of pneumonia events and the number of new users separately to examine the available
precision based on the study design.
Patients will be followed from the date of their first eligible prescription (Cohort Entry
Date) until the earliest of the following: date of study end point (first pneumonia event of
interest), date of treatment end (up to 60-day gap allowed for each inhaler), date of
transfer to a new practice, date of ICS initiation (among LABD new users), death or study
end (end of available data). As part of the primary analysis, patients will be examined for
their first severe pneumonia (severe CAP, HAP). As a secondary analysis, time to non-severe
CAP will be examined. Incidence rates of the pneumonia outcomes will be calculated as the
number of patients experiencing an event divided by the person-years at risk.
Multivariable analysis will be performed using Cox proportional hazard model with adjustment
for confounders and medication exposure. To adjust for differences confounding by severity
due to differences in prescribing between ICS-containing medications and LABD, propensity
scores (PS) will be utilized using inverse probability of treatment weighting (IPTW). The
propensity score will be estimated to model the probability of a patient receiving
ICS-containing medication prescription versus receiving a LABD prescription given a
patient's observed set of baseline covariates.
Effect modification (statistical interaction) will be evaluated based on available theory
and include ICS medication use by known risk factors for pneumonia (BMI<21, BMI 21-24. 9, BMI
≥25, age, GOLD stage III/IV, MRC dyspnea score ≥4, history of pneumonia diagnosis, current
smoking status, social deprivation quartiles). Additional interactions may be evaluated.
To test proportionality of the hazard functions, model diagnostics will be performed.
To compare severe pneumonia with non-severe pneumonia in patients with COPD, characteristics
of patients experiencing non-severe CAP vs. severe CAP or HAP will be tabulated. To assess
differences between treatments, clinical and patient characteristics will be compared using
the chi-square tests or Wilcoxon tests for categorical or continuous data, respectively.
Severe CAP and HAP may be combined. Modeling of clinical and patient characteristics may be
considered using logistic regression using CAP vs. severe CAP and then with severe CAP vs.
HAP.
Additional analysis or adjustments to the analytic or modeling strategy will be performed if
the data warrants. A more detailed modeling strategy, including generation of the
propensity scores and Cox modeling, will be created in a separate analysis plan.
Adjustments to the a priori plan will be described in the final study report.
Clinical Details
Official title: WEUSKOP6416: Evaluating Serious Pneumonia in Subjects With Chronic Obstructive Pulmonary Disease (COPD) to Inform Risk Minimization: A Retrospective Observational Study
Study design: Observational Model: Cohort, Time Perspective: Prospective
Primary outcome: Severe pneumonia: 1) Community-acquired pneumonia (CAP) resulting in hospitalization and/or death.2) hospital-acquired pneumonia (HAP), pneumonia diagnosed >2 days following hospital admission. These outcomes will be examined separately.
Secondary outcome: Non-severe pneumonia: CAP that did not result in hospitalization or death.
Detailed description:
Advantages of the primary care database include the ability to link to secondary care,
Hospital Episode Statistics (HES), and to examine risk factors for pneumonia included in the
UK Quality Outcomes Framework for COPD that are not collected routinely in most other
observational healthcare data sources (e. g., BMI, lung function, smoking history, MRC
dyspnea score). Another advantage of this study is the new-user design, as it minimizes
biases that can be caused by alternative designs which compare events between prevalent user
groups (e. g., survivor bias, covariates altered by prior exposure).
There are also known limitations of observational database analyses where treatments are not
randomized, including the potential for confounding by severity that may not be fully
accounted for in the analysis. ICS-containing medications may be dispensed to patients who
have more severe COPD than patients who are receiving long-acting bronchodilators alone. In
this study, we will adjust for disease severity and patient characteristics in the period
prior to initiation using propensity scores. Medication use in CPRD-GOLD is based on
prescribed medications recorded by the primary care physician, which might not have been
dispensed at the pharmacy or ultimately utilized by the patient. Finally, diagnostic
practices for pneumonia may be different in the UK compared with other countries limiting
the generalizability.
As with any outcome of interest, identifying pneumonia in databases is imperfect and there
may be confusion between diagnoses of pneumonia and influenza or serious exacerbation. To
our knowledge, the relationship between pneumonia recorded in these primary and secondary
care databases have not been investigated. In addition, there is lack of agreement between
pneumonia classification in the absence of chest x-rays, sputum, etc.
Despite the limitations, this study will provide insights into risk factors for serious
pneumonia, including whether ICS modify the effect of established risk factors for serious
pneumonia. The results may identify specific patient groups that are at greatest risk of
serious pneumonia and may identify where risk minimization and/or medical recommendations
may be appropriate.
Eligibility
Minimum age: 45 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- Patients with a Clinical Practice Research Datalink- GP OnLine Data (CPRD-GOLD) of
acceptable research quality
- Patients that are new users of LABD or ICS-containing medications from January
2005-December 2010
- Patients that have a COPD diagnosis at any time in the period prior to and including
the Cohort Entry Date (to eliminate any patients with asthma only)
- Patients that have at least one year of data prior to Cohort Entry Date.
- Patients that are at least 45 years of age at Cohort Entry Date.
- Patients that have Hospital Episode Statistics (HES) linkage.
- Patients that have HES coverage one year prior to the Cohort Entry Date
Exclusion Criteria:
- Patients with an occurrence of a code for a medical condition incompatible with COPD
diagnosis any time in their history will be excluded.
Locations and Contacts
Additional Information
Starting date: July 2012
Last updated: March 9, 2015
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