Asthma, Lung Diseases, Lung Diseases, Obstructive
Conditions
Brief summary
The purpose of this study is to determine if subjects with symptomatic asthma who are assigned to treatment with a proton pump inhibitor (PPI) drug such as Nexium have fewer asthma attacks than similar subjects assigned to placebo treatment.
Detailed description
BACKGROUND: Gastroesophageal reflux (GERD) is frequent in asthmatics with poor asthma control, often occurs without symptoms, and can induce bronchoconstriction. Poorly controlled asthmatics are often treated for GERD with drugs that suppress gastric acid, but this treatment is expensive and the benefit of such treatment is not established. Proton pump inhibitors are a relatively new class of medications that provide highly effective treatment for GERD and associated problems. This success has led many doctors to begin PPI treatment in their asthma patients in an attempt to achieve better asthma control. DESIGN NARRATIVE: The randomized, placebo-controlled trial will enroll 400 asthmatics, ages 18 or older, who have poor asthma control on inhaled steroids, defined on the basis of excessive bronchodilator use, nocturnal awakenings, or frequent exacerbations. Participants will be randomly assigned to treatment with either a proton pump inhibitor, esomeprazole (Nexium) 40 mg twice a day, or matching placebo. The presence, severity, and temporal relationship of GERD to asthma symptoms will be documented with 24 hour ambulatory esophageal potential Hydrogen (pH) probe monitoring, but participants will be enrolled irrespective of the severity of GERD. The primary outcome measure is the proportion of participants who have exacerbations of asthma within a 6-month period defined by asthma diaries and interviews. Secondary outcome measures include asthma symptom and control scores, asthma-specific and generic health-related quality of life, GERD symptoms, health care use, pulmonary function, and airways reactivity. Pre-specified subgroup analyses will be conducted to determine if there are clinical or demographic characteristics that predict benefit from treatment of GERD in asthma.
Interventions
DRUGEsomeprazole
Proton pump inhibitor 40 mg orally twice daily
DRUGPlacebo proton pump inhibitor
Placebo proton pump inhibitor
Sponsors
American Lung Association Asthma Clinical Research Centers
National Heart, Lung, and Blood Institute (NHLBI)
Johns Hopkins Bloomberg School of Public Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The general goal of patient selection is to enroll patients for whom asthma physicians might prescribe GERD treatment, but where there is uncertainty whether it might be effective. * Age 18 or older * Physician diagnosed asthma * If amount of air expired in the first second during a forced expiratory maneuver (FEV1) is greater than or equal to 70% predicted normal pre-bronchodilator: demonstrate methacholine 20% from post-diluent baseline (PC20). PC20 less than 16 mg/ml during Visit 1 * If FEV1 less than 70% and greater than or equal to 50% predicted normal pre-bronchodilator: demonstrate 12% reversibility during Visit 1 or within past 12 months * Currently on stable dose of daily inhaled steroids for asthma control, i.e., inhaled corticosteroid equivalent to 400 ug/day of fluticasone44 or greater for 8 weeks or longer * Poor asthma control: Either of the following; a score of 1.5 or greater on the Juniper Asthma Control Questionnaire; two or more episodes of asthma symptoms in the past 12 months with each episode requiring at least one of the following: an emergency department visit, unscheduled physician visit, prednisone course, hospitalization * Non-smoker for 6 months or longer * Less than 10 pack/year smoking history
Exclusion criteria
* Surgery: Previous anti-reflux or peptic ulcer surgery * Pulmonary function: FEV1 less than 50% predicted normal pre-bronchodilator * GERD Symptoms: Severe reflux constituting a clinical indication for treatment with a PPI or H2 blocker, typically two or more episodes per week of heartburn requiring antacids * Other major chronic illnesses; conditions which in the judgment of the Study Physician would interfere with participation in the study, e.g., non-skin cancer, endocrine disease, coronary artery disease, congestive heart failure, stroke, severe hypertension, Type 1 insulin dependent diabetes mellitus, renal failure, liver disorders, immunodeficiency states, major neuropsychiatric disorder * Medication use: Anti-reflux medication (proton pump inhibitors or H2 blockers) within 1 month Theophylline, azoles, iron, anti-coagulants, insulin (for Type I diabetes), digitalis, any investigative drugs within 1 month * Drug allergy: Previous adverse effects from proton pump inhibitors or methacholine challenge * Females of childbearing potential: Pregnant or lactating, unwilling to practice an adequate birth control method (abstinence, combination barrier and spermicide, or hormonal) * Inability or unwillingness to provide consent * Inability to perform baseline measurements * Completion of less than 10 of the last 14 days of screening period diary entry * Inability to be contacted by telephone * Intention to move out of the area within 6 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Episodes of Poor Asthma Control (EPAC) From Diary Cards, According to Definition That Did Not Include Use of Beta-agonists as a Criterion | Baseline to 24 Weeks | Episodes of poor asthma control was defined as any one of the following: 2 consecutive days with a drop in peak flow \>=30% of baseline; urgent care for asthma; or new use of oral corticosteroids for asthma |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Use of Rescue Medications | Baseline to 24 Weeks | Increase in the use of rescue meds by 4 or more uses on a particular day above the average uses during the run-in period. |
| Exacerbation Components: >=30% Drop in Peak Expiratory Flow on 2 Consecutive Days | Baseline to 24 Weeks | — |
| Exacerbation Components: Urgent Care Visit | Measured at Month 6 | — |
| Exacerbation Components: New Use of Oral Corticosteroids | Baseline to 24 Weeks | — |
| Asthma Episodes, According to Definition That Included Increased Use of Beta-agonists | Baseline to 24 Weeks | — |
| Pulmonary Function: Change in Prebronchodilator FEV1 | Baseline to 24 Weeks | Mean change in pre-bronchodilator FEV1 - forced expiratory volume in 1 second; a measure of pulmonary function. The treatment effect is the difference in the mean change in between the groups. |
| Pulmonary Function: Change in Prebronchodilator Forced Vital Capacity | Baseline to 24 Weeks | Pulmonary function measured by mean change in Prebronchodilator forced vital capacity from baseline to 24 weeks |
| Pulmonary Function: Change in Peak Flow Rate | Baseline to 24 Weeks | Mean change from baseline to 24 weeks in the peak flow rate - how forceful patient can blow out air |
| Night Awakening | Baseline to 24 Weeks | Rate of awakening at night because of asthma symptoms |
| Change in Juniper Asthma Control Score(JACQ) | Baseline to 24 Weeks | Mean change. Scores on the JACQ range from 0 to 6, with lower scores indicating better asthma control and 0.5 as the minimal clinically important difference. |
| Change in Asthma Symptom Utility Index (ASUI) | Baseline to 24 Weeks | Mean change. Scores on the ASUI range from 0 to 1, with higher scores indicating less severe asthma. |
| Change in the Mini-Asthma Quality of Life Questionnaire (Mini-AQLQ) | Baseline to 24 Weeks | Mean change. Scores on the Mini-Asthma Quality of Life Questionnaire (mini-AQLQ)range from 1 to 7, with higher scores indicating better quality of life and 0.5 as the minimal clinically important difference. |
| Change in Medical Outcomes Study Short-Form 36 Score Quality of Life Score: Physical Component | Baseline to 24 Weeks | Mean change. Scores on the Medical Outcomes Study Short-Form 36 range from 1 to 100, with higher scores indicating better quality of life and 5 as the minimal clinically important difference. |
| Change in Medical Outcomes Study Short-Form 36 Quality of Life Score: Mental Component | Baseline to 24 Weeks | Mean change. Scores on the Medical Outcomes Study Short-Form 36 range from 1 to 100, with higher scores indicating better quality of life and 5 as the minimal clinically important difference. |
| Change in Gastric Symptoms: Gastroesophageal Reflux Disease Symptom Assessment Scale Score | Baseline to 24 Weeks | Mean change. The Gastroesophageal Reflux Disease Symptom Assessment Scale score ranges from 0 to 3, with lower numbers indicating less distress. |
| Change in Number of Gastric Symptoms: No. of Symptoms | Baseline to 24 Weeks | Mean change |
| Pulmonary Function: Change in PC20 | Baseline to 24 Weeks | Mean Change in the dose of methacholine that results in a 20% drop in FEV1 |
Countries
United States
Participant flow
Recruitment details
The planned enrollment was for 400 participants, 403 participants actually were enrolled and randomized in the trial. It is not uncommon for clinical trials not to exactly meet the sample size stated in the protocol.
Participants by arm
| Arm | Count |
|---|---|
| Placebo 40 mg of placebo twice daily | 199 |
| Esomeprazole 40 mg of esomeprazole twice daily | 203 |
| Total | 402 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Did not have follow-up diary cards | 6 | 3 |
Baseline characteristics
| Characteristic | Placebo | Total | Esomeprazole |
|---|---|---|---|
| Age Continuous | 42 years STANDARD_DEVIATION 13 | 42 years STANDARD_DEVIATION 13 | 42 years STANDARD_DEVIATION 13 |
| Age of onset of asthma | 17 years STANDARD_DEVIATION 17 | 17 years STANDARD_DEVIATION 16 | 17 years STANDARD_DEVIATION 16 |
| Age of participants at onset of asthma | 17 years STANDARD_DEVIATION 17 | 17 years STANDARD_DEVIATION 16 | 17 years STANDARD_DEVIATION 16 |
| Age of participants at randomization | 42 years STANDARD_DEVIATION 13 | 42 years STANDARD_DEVIATION 13 | 42 years STANDARD_DEVIATION 13 |
| Asthma medication use Combination of fluticasone and salmeterol | 149 participants | 308 participants | 159 participants |
| Asthma medication use Inhaled corticosteroids | 50 participants | 94 participants | 44 participants |
| Asthma scores ACQ | 1.9 score STANDARD_DEVIATION 0.8 | 1.8 score STANDARD_DEVIATION 0.8 | 1.8 score STANDARD_DEVIATION 0.8 |
| Asthma scores ASUI | 0.74 score STANDARD_DEVIATION 0.18 | 0.75 score STANDARD_DEVIATION 0.15 | 0.76 score STANDARD_DEVIATION 0.15 |
| Asthma scores mini asthma quality of life questionnaire | 4.7 score STANDARD_DEVIATION 1.2 | 4.7 score STANDARD_DEVIATION 1.2 | 4.7 score STANDARD_DEVIATION 1.2 |
| Body-mass index >=30 BMI <30 | 92 participants | 193 participants | 101 participants |
| Body-mass index >=30 BMI >=30 | 107 participants | 209 participants | 102 participants |
| Conditions other than asthma Gastroesophageal reflux disease | 38 participants | 59 participants | 21 participants |
| Conditions other than asthma No GER reported | 161 participants | 343 participants | 182 participants |
| Former smoker Former Smoker | 40 participants | 71 participants | 31 participants |
| Former smoker Never smoked | 159 participants | 331 participants | 172 participants |
| Health Care Visits Health care visit for asthma exacerbation | 126 participants | 235 participants | 109 participants |
| Health Care Visits No visit | 73 participants | 167 participants | 94 participants |
| Percent change in FEV1 after bronchodilator | 10 Percent change STANDARD_DEVIATION 10 | 11 Percent change STANDARD_DEVIATION 13 | 11 Percent change STANDARD_DEVIATION 16 |
| potential Hydrogen (pH) monitoring Missing result | 48 participants | 98 participants | 50 participants |
| potential Hydrogen (pH) monitoring Negative result | 89 participants | 181 participants | 92 participants |
| potential Hydrogen (pH) monitoring Positive result | 62 participants | 123 participants | 61 participants |
| %Predicted amount of air expired in the first second during a forced expiration pre broncho-dilator | 78 Percent STANDARD_DEVIATION 15 | 77 Percent STANDARD_DEVIATION 16 | 76 Percent STANDARD_DEVIATION 16 |
| Pulmonary function 20% from post-diluent contraindicated | 102 participants | 219 participants | 117 participants |
| Pulmonary function Missing | 5 participants | 8 participants | 3 participants |
| Pulmonary function Participants with 20% post-diluent measurement | 92 participants | 175 participants | 83 participants |
| Race/Ethnicity, Customized Black | 73 participants | 152 participants | 79 participants |
| Race/Ethnicity, Customized Hispanic | 17 participants | 35 participants | 18 participants |
| Race/Ethnicity, Customized Other | 6 participants | 10 participants | 4 participants |
| Race/Ethnicity, Customized White | 103 participants | 205 participants | 102 participants |
| Sex: Female, Male Female | 143 Participants | 273 Participants | 130 Participants |
| Sex: Female, Male Male | 56 Participants | 129 Participants | 73 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 199 | 0 / 203 |
| serious Total, serious adverse events | 16 / 199 | 10 / 203 |
Outcome results
Primary
Episodes of Poor Asthma Control (EPAC) From Diary Cards, According to Definition That Did Not Include Use of Beta-agonists as a Criterion
Episodes of poor asthma control was defined as any one of the following: 2 consecutive days with a drop in peak flow \>=30% of baseline; urgent care for asthma; or new use of oral corticosteroids for asthma
Time frame: Baseline to 24 Weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Episodes of Poor Asthma Control (EPAC) From Diary Cards, According to Definition That Did Not Include Use of Beta-agonists as a Criterion | 2.3 events per person year |
| Esomeprazole | Episodes of Poor Asthma Control (EPAC) From Diary Cards, According to Definition That Did Not Include Use of Beta-agonists as a Criterion | 2.5 events per person year |
Comparison: The rates of EPACs were compared using incidence-rate ratios (IRR). IRR and P value were estimated with the use of negative binomial regression models with robust variance estimates.p-value: 0.6695% CI: [0.8, 1.5]Negative binomial regression
Secondary
Asthma Episodes, According to Definition That Included Increased Use of Beta-agonists
Time frame: Baseline to 24 Weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Asthma Episodes, According to Definition That Included Increased Use of Beta-agonists | 4.4 events per person-year |
| Esomeprazole | Asthma Episodes, According to Definition That Included Increased Use of Beta-agonists | 4.3 events per person-year |
Comparison: Rates were compared with incidence-rate ratios (IRR). The IRR and P values were estimated with the use of negative binomial regression models with robust variance estimates.p-value: 0.8795% CI: [0.8, 1.3]Negative binomial regression
Secondary
Change in Asthma Symptom Utility Index (ASUI)
Mean change. Scores on the ASUI range from 0 to 1, with higher scores indicating less severe asthma.
Time frame: Baseline to 24 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Change in Asthma Symptom Utility Index (ASUI) | 0.05 score |
| Esomeprazole | Change in Asthma Symptom Utility Index (ASUI) | 0.02 score |
p-value: 0.1195% CI: [-0.05, -0.02]Regression, Linear
Secondary
Change in Gastric Symptoms: Gastroesophageal Reflux Disease Symptom Assessment Scale Score
Mean change. The Gastroesophageal Reflux Disease Symptom Assessment Scale score ranges from 0 to 3, with lower numbers indicating less distress.
Time frame: Baseline to 24 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Change in Gastric Symptoms: Gastroesophageal Reflux Disease Symptom Assessment Scale Score | -0.17 score |
| Esomeprazole | Change in Gastric Symptoms: Gastroesophageal Reflux Disease Symptom Assessment Scale Score | -0.16 score |
p-value: 0.7695% CI: [-0.05, 0.07]Regression, Linear
Secondary
Change in Juniper Asthma Control Score(JACQ)
Mean change. Scores on the JACQ range from 0 to 6, with lower scores indicating better asthma control and 0.5 as the minimal clinically important difference.
Time frame: Baseline to 24 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Change in Juniper Asthma Control Score(JACQ) | -0.3 score |
| Esomeprazole | Change in Juniper Asthma Control Score(JACQ) | -0.2 score |
p-value: 0.1195% CI: [0, 0.2]Regression, Linear
Secondary
Change in Medical Outcomes Study Short-Form 36 Quality of Life Score: Mental Component
Mean change. Scores on the Medical Outcomes Study Short-Form 36 range from 1 to 100, with higher scores indicating better quality of life and 5 as the minimal clinically important difference.
Time frame: Baseline to 24 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Change in Medical Outcomes Study Short-Form 36 Quality of Life Score: Mental Component | 0.0 score |
| Esomeprazole | Change in Medical Outcomes Study Short-Form 36 Quality of Life Score: Mental Component | 0.4 score |
p-value: 0.5695% CI: [-1.1, 2.2]Regression, Linear
Secondary
Change in Medical Outcomes Study Short-Form 36 Score Quality of Life Score: Physical Component
Mean change. Scores on the Medical Outcomes Study Short-Form 36 range from 1 to 100, with higher scores indicating better quality of life and 5 as the minimal clinically important difference.
Time frame: Baseline to 24 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Change in Medical Outcomes Study Short-Form 36 Score Quality of Life Score: Physical Component | 2.0 score |
| Esomeprazole | Change in Medical Outcomes Study Short-Form 36 Score Quality of Life Score: Physical Component | 1.1 score |
p-value: 0.1695% CI: [-2, 0.4]Regression, Linear
Secondary
Change in Number of Gastric Symptoms: No. of Symptoms
Mean change
Time frame: Baseline to 24 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Change in Number of Gastric Symptoms: No. of Symptoms | -1.7 symptoms |
| Esomeprazole | Change in Number of Gastric Symptoms: No. of Symptoms | -1.9 symptoms |
p-value: 0.3995% CI: [-0.8, 0.3]Regression, Linear
Secondary
Change in the Mini-Asthma Quality of Life Questionnaire (Mini-AQLQ)
Mean change. Scores on the Mini-Asthma Quality of Life Questionnaire (mini-AQLQ)range from 1 to 7, with higher scores indicating better quality of life and 0.5 as the minimal clinically important difference.
Time frame: Baseline to 24 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Change in the Mini-Asthma Quality of Life Questionnaire (Mini-AQLQ) | 0.3 score |
| Esomeprazole | Change in the Mini-Asthma Quality of Life Questionnaire (Mini-AQLQ) | 0.3 score |
p-value: 0.3395% CI: [-0.2, 0.1]Regression, Linear
Secondary
Exacerbation Components: >=30% Drop in Peak Expiratory Flow on 2 Consecutive Days
Time frame: Baseline to 24 Weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Exacerbation Components: >=30% Drop in Peak Expiratory Flow on 2 Consecutive Days | 1.7 events per person-year |
| Esomeprazole | Exacerbation Components: >=30% Drop in Peak Expiratory Flow on 2 Consecutive Days | 2.1 events per person-year |
Comparison: Rates were compared with incidence-rate ratios (IRR). The IRR and P values were estimated with the use of negative binomial regression models with robust variance estimates.p-value: 0.3595% CI: [0.8, 2]Negative binomial regression
Secondary
Exacerbation Components: New Use of Oral Corticosteroids
Time frame: Baseline to 24 Weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Exacerbation Components: New Use of Oral Corticosteroids | 0.6 events per person year |
| Esomeprazole | Exacerbation Components: New Use of Oral Corticosteroids | 0.5 events per person year |
Comparison: Rates were compared with incidence-rate ratios (IRR). The IRR and P values were estimated with the use of negative binomial regression models with robust variance estimates.p-value: 0.6295% CI: [0.6, 1.3]Negative binomial regression
Secondary
Exacerbation Components: Urgent Care Visit
Time frame: Measured at Month 6
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Exacerbation Components: Urgent Care Visit | 0.6 events per person-year |
| Esomeprazole | Exacerbation Components: Urgent Care Visit | 0.5 events per person-year |
Comparison: Rates were compared with incidence-rate ratios (IRR). The IRR and P values were estimated with the use of negative binomial regression models with robust variance estimates.p-value: 0.7995% CI: [0.6, 1.5]Negative binomial regression
Secondary
Night Awakening
Rate of awakening at night because of asthma symptoms
Time frame: Baseline to 24 Weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Night Awakening | 30 events per person-year |
| Esomeprazole | Night Awakening | 28 events per person-year |
Comparison: Incidence-rate ratios and P values were estimated with the use of negative binomial regression models with robust variance estimates.p-value: 0.795% CI: [0.6, 1.4]Negative binomial regression
Secondary
Pulmonary Function: Change in PC20
Mean Change in the dose of methacholine that results in a 20% drop in FEV1
Time frame: Baseline to 24 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Pulmonary Function: Change in PC20 | 1.5 mg/ml |
| Esomeprazole | Pulmonary Function: Change in PC20 | 0.3 mg/ml |
p-value: 0.0495% CI: [-3.6, -0.1]Regression, Linear
Secondary
Pulmonary Function: Change in Peak Flow Rate
Mean change from baseline to 24 weeks in the peak flow rate - how forceful patient can blow out air
Time frame: Baseline to 24 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Pulmonary Function: Change in Peak Flow Rate | 3.2 liters/min |
| Esomeprazole | Pulmonary Function: Change in Peak Flow Rate | 9.2 liters/min |
p-value: 0.2495% CI: [-4, 16]Regression, Linear
Secondary
Pulmonary Function: Change in Prebronchodilator FEV1
Mean change in pre-bronchodilator FEV1 - forced expiratory volume in 1 second; a measure of pulmonary function. The treatment effect is the difference in the mean change in between the groups.
Time frame: Baseline to 24 Weeks
Population: The analyses are based on data from 191 participants in the placebo group and 201 in the esomeprazole group, with the following exception: 41 participants in the placebo group and 37 in the esomeprazole group for measurement of 20% post-diluent baseline (PC20).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Pulmonary Function: Change in Prebronchodilator FEV1 | -0.02 liters |
| Esomeprazole | Pulmonary Function: Change in Prebronchodilator FEV1 | 0.00 liters |
Comparison: The treatment effect is the mean change in the Esomeprazole group - mean change in placebo groupp-value: 0.3695% CI: [-0.03, 0.08]Regression, Linear
Secondary
Pulmonary Function: Change in Prebronchodilator Forced Vital Capacity
Pulmonary function measured by mean change in Prebronchodilator forced vital capacity from baseline to 24 weeks
Time frame: Baseline to 24 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Pulmonary Function: Change in Prebronchodilator Forced Vital Capacity | -0.03 liters |
| Esomeprazole | Pulmonary Function: Change in Prebronchodilator Forced Vital Capacity | 0.00 liters |
p-value: 0.395% CI: [-0.03, 0.09]Regression, Linear
Secondary
Use of Rescue Medications
Increase in the use of rescue meds by 4 or more uses on a particular day above the average uses during the run-in period.
Time frame: Baseline to 24 Weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Use of Rescue Medications | 3.0 events per person-year |
| Esomeprazole | Use of Rescue Medications | 2.8 events per person-year |
Comparison: Incidence-rate ratios and P values were estimated with the use of negative binomial regression models with robust variance estimates.p-value: 0.6295% CI: [0.7, 1.3]Negative binomial regression