Pulmonary Disease, Chronic Obstructive
Conditions
Keywords
Chronic Obstructive Pulmonary Disease, COPD, Exacerbation, Anti-leukotriene, Length of Stay, LOS
Brief summary
Chronic obstructive pulmonary disease (COPD) is a long-term lung disease that is caused by cigarette smoking or by breathing in other lung irritants, including pollution, dust, or chemicals. The purpose of this study is to evaluate the effectiveness of zileuton, a medication that is used to control asthma symptoms, at reducing the length of a hospital stay for adults who are hospitalized for a COPD exacerbation, or worsening of COPD symptoms.
Detailed description
COPD is a disease in which the lung airways are partly damaged and obstructed, making it difficult to breathe. COPD is the fourth leading cause of death in the United States. Symptoms include coughing, excess mucus production, shortness of breath, wheezing, and chest tightness. Treatment usually includes inhaled bronchodilator or steroid medications that work by relaxing the muscles around the lung airways and reducing inflammation. Zileuton, a medication that is used to prevent asthma symptoms, may be beneficial in treating people who experience COPD exacerbations. Zileuton works by blocking the formation of substances that cause inflammation, fluid retention, and constriction in the lungs. The purpose of this study is to evaluate the effectiveness of zileuton at reducing the length of a hospital stay for adults who are hospitalized for a COPD exacerbation. This study will enroll adults who are admitted to the hospital due to severe COPD symptoms. Participants will be randomly assigned to receive either zileuton or placebo four times a day for up to 14 days. While in the hospital, lung function testing and urine collection will occur. Study visits will occur at Days 14 and 30, and will include lung function testing, a medical history review, and a study drug adverse effects review.
Interventions
DRUGZileuton
Zyflo tablets, 600 mg, 4 times a day
DRUGPlacebo
Placebo 4 x daily
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
45 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Admitted to the hospital for a COPD exacerbation * FEV1 less than 60% of predicted level * At least 10 pack years of smoking
Exclusion criteria
* Any uncontrolled systemic disease * Known hypersensitivity to zileuton * Asthma * Lobar pneumonia or pulmonary edema * Interstitial lung disease * Medical condition that is likely to limit survival to less than 30 days at the time of study entry * History of liver disease * Current use of theophylline * Participation in another clinical trial in the COPD Clinical Research Network * Incarceration * Institutionalization * Pregnant * History of a suicide attempt * Prior inpatient admission for a psychiatric disorder * Bipolar disorder '
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Length of Hospital Stay | Measured at Day 30 | Admission will begin at the time the subject has been admitted to an inpatient service. Length of Stay (LOS) will be recorded in days. The LOS will be based on the number of days spent in an acute medical ward or in the ICU. Subjects that are admitted and discharged in the same 24 hour period will be recorded as a LOS of 1 day, as will subjects discharged in the ensuing 24 hour period. LOS's greater than 10 days will be truncated to 10 days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in FEV1% Predicted | Measured at Baseline and Day 30 | Change in Post-bronchodilator FEV1% predicted comparing data at 30 day visit with baseline. |
| Change in FEV1/FEV6 Levels | from baseline to day of discharge | Change in Post-bronchodilator FEV1/FEV6 ratio comparing data at discharge visit with baseline. |
| Treatment Failure | Baseline to day 30 visit | Treatment failure is defined as death, intubation, readmission to a hospital for COPD, urgent visit to an outpatient or ED provider for symptoms of COPD or intensification of therapy \[including second course of antibiotics for COPD, and second course of systemic steroids for COPD\]) in the first 30 days after randomization. |
| Health-related Quality of Life | Change from Baseline and 1 Month | St. George's Respiratory Questionnaire - Total Score The SGRQ was asked with respect to the last one month as validated for acute exacerbations of COPD by Doll et al. Scale from 0 (no disability) to 100 (maximum disability). The SGRQ total score summarizes the impact of airway specific disease on overall health status. Scores range from zero (no impairment) to 100 (maximum impairment). Scores were calculated using the SGRQ scoring Algorithm. |
| Change in Urinary Leukotriene (LTE4) Levels | Baseline and 24 hours | Change in natural log-transformed LTE4 (ng/mg Cr.) from Baseline to 24 Hours |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from ER's and inpatient units from 10 main clinical sites (and their affiliated hospitals) between September 2007 and October 2008.
Pre-assignment details
Participants were screened using the eligibility criteria before randomization.
Participants by arm
| Arm | Count |
|---|---|
| Zileuton Zileuton (Zyflo, 600 mg 4 times a day) | 60 |
| Placebo Matching placebo 4 times a day | 59 |
| Total | 119 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 2 |
| Overall Study | Lost to Follow-up | 4 | 6 |
| Overall Study | Withdrawal by Subject | 8 | 6 |
Baseline characteristics
| Characteristic | Total | Placebo | Zileuton |
|---|---|---|---|
| Age, Continuous | 63.2 years STANDARD_DEVIATION 8.9 | 64.3 years STANDARD_DEVIATION 9.5 | 62.2 years STANDARD_DEVIATION 8.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 113 Participants | 57 Participants | 56 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 40 Participants | 24 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 10 Participants | 3 Participants | 7 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 67 Participants | 31 Participants | 36 Participants |
| Sex: Female, Male Female | 41 Participants | 18 Participants | 23 Participants |
| Sex: Female, Male Male | 78 Participants | 41 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 60 | 12 / 59 |
| serious Total, serious adverse events | 17 / 60 | 20 / 59 |
Outcome results
Primary
Length of Hospital Stay
Admission will begin at the time the subject has been admitted to an inpatient service. Length of Stay (LOS) will be recorded in days. The LOS will be based on the number of days spent in an acute medical ward or in the ICU. Subjects that are admitted and discharged in the same 24 hour period will be recorded as a LOS of 1 day, as will subjects discharged in the ensuing 24 hour period. LOS's greater than 10 days will be truncated to 10 days.
Time frame: Measured at Day 30
Population: Participants were analyzed following intention to treat (ITT) method.~One participant randomized to Zileuton withdrew consent before hospital discharge.~Days to discharge are set at a maximum of 10 days.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Zileuton | Length of Hospital Stay | 3 Days | Standard Deviation 2.19 |
| Placebo | Length of Hospital Stay | 3 Days | Standard Deviation 3.06 |
p-value: 0.3876Wilcoxon (Mann-Whitney)
Secondary
Change in FEV1/FEV6 Levels
Change in Post-bronchodilator FEV1/FEV6 ratio comparing data at discharge visit with baseline.
Time frame: from baseline to day of discharge
Population: Participants were analyzed using the intent to treat method. The N is lower than total randomized due to participants that were unable to perform spirometry at baseline and missing discharge data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zileuton | Change in FEV1/FEV6 Levels | 0.02 ratio | Standard Error 0.03 |
| Placebo | Change in FEV1/FEV6 Levels | 0.03 ratio | Standard Error 0.02 |
p-value: 0.6433Wilcoxon (Mann-Whitney)
Secondary
Change in FEV1% Predicted
Change in Post-bronchodilator FEV1% predicted comparing data at 30 day visit with baseline.
Time frame: Measured at Baseline and Day 30
Population: Participants were analyzed using the intent to treat method. The N is lower than total randomized due to participants that were unable to perform spirometry at baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zileuton | Change in FEV1% Predicted | 6.8 percent predicted | Standard Error 4.2 |
| Placebo | Change in FEV1% Predicted | 8.0 percent predicted | Standard Error 4.4 |
p-value: 0.6413Wilcoxon (Mann-Whitney)
Secondary
Change in Urinary Leukotriene (LTE4) Levels
Change in natural log-transformed LTE4 (ng/mg Cr.) from Baseline to 24 Hours
Time frame: Baseline and 24 hours
Population: Intent to Treat.~Participants with urine sample at both visits.
| Arm | Measure | Value (LOG_MEAN) | Dispersion |
|---|---|---|---|
| Zileuton | Change in Urinary Leukotriene (LTE4) Levels | -1.38 (ng/mg Cr.) | Standard Error 0.17 |
| Placebo | Change in Urinary Leukotriene (LTE4) Levels | 0.14 (ng/mg Cr.) | Standard Error 0.22 |
p-value: <0.0001t-test, 2 sided
Secondary
Change in Urinary Leukotriene (LTE4) Levels
Change in natural log-transformed LTE4 (ng/mg Cr.) from Baseline to 72 Hours
Time frame: Baseline and 72 hours later
Population: Intent to Treat.~Participants with urine sample at both visits.
| Arm | Measure | Value (LOG_MEAN) | Dispersion |
|---|---|---|---|
| Zileuton | Change in Urinary Leukotriene (LTE4) Levels | -1.32 (ng/mg Cr.) | Standard Error 0.4 |
| Placebo | Change in Urinary Leukotriene (LTE4) Levels | 0.26 (ng/mg Cr.) | Standard Error 0.38 |
p-value: 0.006t-test, 2 sided
Secondary
Health-related Quality of Life
St. George's Respiratory Questionnaire - Total Score The SGRQ was asked with respect to the last one month as validated for acute exacerbations of COPD by Doll et al. Scale from 0 (no disability) to 100 (maximum disability). The SGRQ total score summarizes the impact of airway specific disease on overall health status. Scores range from zero (no impairment) to 100 (maximum impairment). Scores were calculated using the SGRQ scoring Algorithm.
Time frame: Change from Baseline and 1 Month
Population: Participants were analyzed using the intent to treat method and included those that had SGRQ data at baseline and 1 month.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zileuton | Health-related Quality of Life | -10.6 Units on a scale | Standard Deviation 14.8 |
| Placebo | Health-related Quality of Life | -8.5 Units on a scale | Standard Deviation 14.6 |
p-value: 0.4957t-test, 2 sided
Secondary
Treatment Failure
Treatment failure is defined as death, intubation, readmission to a hospital for COPD, urgent visit to an outpatient or ED provider for symptoms of COPD or intensification of therapy \[including second course of antibiotics for COPD, and second course of systemic steroids for COPD\]) in the first 30 days after randomization.
Time frame: Baseline to day 30 visit
Population: Participants were analyzed following intention to treat (ITT) method.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zileuton | Treatment Failure | Urgent Visit | 7 Participants |
| Zileuton | Treatment Failure | Intubation | 1 Participants |
| Zileuton | Treatment Failure | Intensification of therapy | 11 Participants |
| Zileuton | Treatment Failure | Hospital Readmission | 7 Participants |
| Zileuton | Treatment Failure | Any Treatment Failure | 14 Participants |
| Zileuton | Treatment Failure | Death | 1 Participants |
| Placebo | Treatment Failure | Any Treatment Failure | 16 Participants |
| Placebo | Treatment Failure | Hospital Readmission | 7 Participants |
| Placebo | Treatment Failure | Urgent Visit | 6 Participants |
| Placebo | Treatment Failure | Death | 2 Participants |
| Placebo | Treatment Failure | Intensification of therapy | 11 Participants |
| Placebo | Treatment Failure | Intubation | 1 Participants |
p-value: 0.63Chi-squared