Asthma, Wheezing
Conditions
Keywords
Asthma, Wheezing, Ibuprofen, Acetaminophen, exacerbations, pain, fever
Brief summary
The Acetaminophen Versus Ibuprofen in Children with Asthma study will test the primary hypothesis that in preschool children 12-59 months of age with persistent asthma on standardized asthma therapy, the number of asthma exacerbations requiring systemic corticosteroids will be more frequent in children randomized to receive acetaminophen as compared to those randomized to receive ibuprofen on an as needed basis for fevers and pain.
Detailed description
AVICA is a 48-week randomized therapeutic trial involving two parallel treatment arms: acetaminophen and ibuprofen. Participating children will be randomized to receive either acetaminophen or ibuprofen administered as needed per parental decision for fever and analgesia. This study will address which is the most appropriate antipyretic-analgesic medication in young children with asthma, and will inform both clinicians and parents seeking to treat children with fever and pain. Given the high frequency of administration of these drugs, this study will have a significant impact on pediatric healthcare regardless of whether a differential effect is discovered as significant uncertainty currently exists as to whether acetaminophen use is associated with increased asthma symptoms.
Interventions
DRUGAcetaminophen
15 mg/kg every 6 hours as needed
DRUGIbuprofen
9.4 mg/kg every 6 hours as needed
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Milton S. Hershey Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Months to 59 Months
Healthy volunteers
No
Inclusion criteria
* 12-59 months of age. * If the child is not currently taking long-term asthma controller therapy (meaning that the child has taken no inhaled corticosteroid or leukotriene receptor antagonist medication whatsoever over the past 6 months), then one of the following criteria must be met: * Daytime asthma symptoms more than two days per week (average over the past 4 weeks), * At least one nighttime awakening from asthma (over the past 4 weeks), * Two or more asthma exacerbations requiring systemic corticosteroids in the previous 6 months, * Four or more wheezing episodes in the previous 12 months. * If the child is currently taking long-term asthma controller therapy (meaning that the child has taken daily or intermittent/as-needed inhaled corticosteroid or leukotriene receptor antagonist over the past 6 months), then one of the following criteria must be met: * Taking inhaled corticosteroid or leukotriene receptor antagonist for more than 3 months (or more than 90 days) out of the previous 6 months (or 180 days), * Daytime asthma symptoms more than two days per week (average over the past 4 weeks), * More than one nighttime awakening from asthma (over the past 4 weeks), * Two or more asthma exacerbations requiring systemic corticosteroids in the previous 12 months, * Four or more wheezing episodes in the previous 12 months. * Up to date with immunizations, including varicella (unless the subject has already had clinical varicella). * Willingness to provide informed consent by the child's parent or guardian.
Exclusion criteria
* Allergic reaction to the study medications or any component of the study drugs, including (but not limited to) urticaria, rash, angioedema, or hypotension following delivery, * Chronic medical disorders that could interfere with drug metabolism/excretion (for instance chronic hepatic, biliary, or renal disease), * Chronic medical disorders that may increase the risk of drug-related injury, including (but not limited to): * Osteogenesis imperfecta (increased risk of bone demineralization/fracture with corticosteroid therapy), * Crohn's disease, ulcerative colitis, juvenile rheumatoid arthritis, clotting disorders, or Factor deficiency (increased risk of bleeding with corticosteroid therapy), * G6PD deficiency (increased risk of hemolytic anemia with acetaminophen use), * Phenylketonuria (potential for aspartame exposure with study interventions), * Seizure disorder treated with anticonvulsants (risk of acetaminophen toxicity with carbamazepine), or * History of clotting disorders or Factor deficiency (increased risk of bleeding with corticosteroids), * Co-morbid disorders associated with wheezing including (but not limited to) immune deficiency disorders, cystic fibrosis, aspiration, clinically-relevant gastroesophageal reflux, tracheomalacia, congenital airway anomalies (clefts, fistulas, slings, rings), bronchiectasis, bronchopulmonary dysplasia, and/or history of premature birth before 35 weeks gestation, * Significant developmental delay/failure to thrive, defined as 5th percentile for height and/or weight or crossing of two major percentile lines during the last year for age and sex, * History of a near-fatal asthma exacerbation requiring intubation or assisted ventilation, * No primary medical caregiver (e.g., a nurse practitioner, physician assistant, physician, or group medical practice such as a hospital-based clinic) whom the subject can contact for primary medical care, * Three or more hospitalizations in the previous 12 months for wheezing or respiratory illnesses, * Treatment with 5 or more courses of systemic corticosteroids (oral, intramuscular or intravenous) in the past 6 months, * Current use of higher than step 2 NAEPP asthma guideline therapy * If receiving allergy shots, change in the dose within the past 3 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Exacerbation Frequency | last 46 weeks of 48 week treatment period | the number of asthma exacerbations requiring systemic corticosteroids |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Asthma Control Days | last 46 weeks of 48 week treatment period | proportion of study days on which asthma was controlled, measured by electronic diary |
| Asthma Rescue Medication Use | last 46 weeks of 48 week treatment period | average albuterol rescue use per week, measured by electronic diary |
| Health Care Utilization | last 46 weeks of 48 week treatment period | frequency of unscheduled physician visits, emergency department visits or hospitalizations for asthma |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Acetaminophen acetaminophen given as needed for pain or fever
Acetaminophen: 15 mg/kg every 6 hours as needed | 150 |
| Ibuprofen ibuprofen given as needed for pain or fever
Ibuprofen: 9.4 mg/kg every 6 hours as needed | 150 |
| Total | 300 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 4 |
| Overall Study | Lack of Efficacy | 6 | 8 |
| Overall Study | Lost to Follow-up | 17 | 14 |
| Overall Study | Physician Decision | 1 | 2 |
| Overall Study | Withdrawal by Subject | 9 | 12 |
Baseline characteristics
| Characteristic | Ibuprofen | Total | Acetaminophen |
|---|---|---|---|
| Age, Continuous | 39.4 months STANDARD_DEVIATION 13.6 | 39.9 months STANDARD_DEVIATION 13.2 | 40.3 months STANDARD_DEVIATION 12.9 |
| Allergen Test Negative test | 88 participants | 174 participants | 86 participants |
| Allergen Test Positive test | 62 participants | 126 participants | 64 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 37 Participants | 72 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 113 Participants | 228 Participants | 115 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Gender Female | 57 Participants | 121 Participants | 64 Participants |
| Gender Male | 93 Participants | 179 Participants | 86 Participants |
| IgE (kU/L) | 70 kU/L | 70 kU/L | 64 kU/L |
| Number of Oral Corticosteroid (OCS) courses in the past 6 months | 1.2 OCS courses per 6 months STANDARD_DEVIATION 1 | 1.1 OCS courses per 6 months STANDARD_DEVIATION 1.1 | 1 OCS courses per 6 months STANDARD_DEVIATION 1.1 |
| Number of urgent care and ED visits in the past year | 3.0 urgent care/ED visits per year STANDARD_DEVIATION 2.3 | 3.1 urgent care/ED visits per year STANDARD_DEVIATION 2.4 | 3.1 urgent care/ED visits per year STANDARD_DEVIATION 2.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 50 Participants | 97 Participants | 47 Participants |
| Race (NIH/OMB) More than one race | 23 Participants | 45 Participants | 22 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 74 Participants | 148 Participants | 74 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 135 / 150 | 124 / 150 |
| serious Total, serious adverse events | 6 / 150 | 12 / 150 |
Outcome results
Primary
Exacerbation Frequency
the number of asthma exacerbations requiring systemic corticosteroids
Time frame: last 46 weeks of 48 week treatment period
Population: Two participants in the ibuprofen arm dropped out of the study during the first two weeks of the study and were not included in the analysis per the pre-specified analysis plan.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Acetaminophen | Exacerbation Frequency | 0.81 asthma exacerbations per 46 weeks |
| Ibuprofen | Exacerbation Frequency | .87 asthma exacerbations per 46 weeks |
p-value: 0.6795% CI: [0.69, 1.28]log-linear model
Secondary
Asthma Control Days
proportion of study days on which asthma was controlled, measured by electronic diary
Time frame: last 46 weeks of 48 week treatment period
Population: Two participants in the ibuprofen arm dropped out of the study during the first two weeks of the study and were not included in the analysis per the pre-specified analysis plan.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Acetaminophen | Asthma Control Days | .86 proportion of days |
| Ibuprofen | Asthma Control Days | .87 proportion of days |
p-value: 0.595% CI: [-0.039, 0.0019]ANCOVA
Secondary
Asthma Rescue Medication Use
average albuterol rescue use per week, measured by electronic diary
Time frame: last 46 weeks of 48 week treatment period
Population: Two participants in the ibuprofen arm dropped out of the study during the first two weeks of the study and were not included in the analysis per the pre-specified analysis plan.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Acetaminophen | Asthma Rescue Medication Use | 2.8 inhalations per week |
| Ibuprofen | Asthma Rescue Medication Use | 3 inhalations per week |
p-value: 0.6995% CI: [-0.9, 0.6]ANCOVA
Secondary
Health Care Utilization
frequency of unscheduled physician visits, emergency department visits or hospitalizations for asthma
Time frame: last 46 weeks of 48 week treatment period
Population: Two participants in the ibuprofen arm dropped out of the study during the first two weeks of the study and were not included in the analysis per the pre-specified analysis plan.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Acetaminophen | Health Care Utilization | .75 unscheduled health visits per 46 weeks |
| Ibuprofen | Health Care Utilization | .76 unscheduled health visits per 46 weeks |
p-value: 0.9495% CI: [0.72, 1.37]log-linear model