Additional Study Information

This study is comprised of two separate, but linked, clinical trials for treating young children with mild persistent asthma.

Objectives

The INFANT study aimed to determine whether individual young children with mild persistent asthma responded better to daily inhaled corticosteroids, daily leukotriene receptor antagonist, or as-needed inhaled corticosteroids and, if treatment response can be identified by phenotypic characteristics. The AVICA study compared the use of acetaminophen to the use of ibuprofen on asthma exacerbations among young children with mild persistent asthma.

Background

Although asthma treatment guidelines have proved useful in care standardization and reduction of adverse outcomes, there is phenotypic heterogeneity within the disorder and a growing appreciation for personalized medicine. Young children are particularly diverse, yet, at the time of this trial, they were incompletely studied. Among young children who warrant treatment with daily inhaled corticosteroids (ICS), the response to ICS is inconsistent. This raises the question of whether daily therapy with ICS is warranted in all children. Therefore, INFANT characterized phenotypic heterogeneity in young children with mild persistent asthma and determined whether individual children responded better to daily ICS, daily leukotriene receptor antagonist (LTRA), or as-needed ICS co-administered with a short-acting bronchodilator.

Observational data from pediatric cohorts have suggested an association between acetaminophen use and asthma-related complications. However, at the time of the AVICA study appropriately designed randomized trials that prospectively evaluated the association between acetaminophen use by children and asthma symptoms were lacking. Given that both acetaminophen and ibuprofen are the only readily available agents for fever or pain in young children, the AVICA study sought to investigate whether the use of acetaminophen, compared to the use of ibuprofen, was associated with higher morbidity related to asthma among young children with mild persistent asthma.

Participants

The INFANT and AVICA linked studies were conducted in children 12 to 59 months of age at 18 sites in the United States. Children were eligible for study entry if they met guideline-based criteria for daily asthma controller medication (Step 2 treatment) and they reported ICS or LTRA receipt for >90 days during the preceding 6 months or ≥2 exacerbations requiring systemic corticosteroids in the preceding 12 months. Children not receiving current ICS or LTRA treatment were eligible if they reported ≥2 exacerbations requiring systemic corticosteroids in the preceding 6 months. Children were also eligible irrespective of current medication use if their caregivers reported daytime asthma symptoms >2 days per week (averaged over the preceding 4 weeks), nighttime awakening from asthma at least once over the previous 4 weeks, or ≥4 wheezing episodes, each lasting ≥24 hours, in the preceding 12 months.

300 children were simultaneously randomized to an INFANT study crossover sequence of treatments and an AVICA study antipyretic, analgesic medication. 230 children completed at least two study periods in the INFANT trial permitting assessment of differential response. In the AVICA study, 150 children were assigned to the acetaminophen treatment group and 150 children were assigned to the ibuprofen group. A total of 226 children completed the AVICA trial.

Design

The INFANT study was a multicenter, randomized, double-blind clinical trial with the AVICA study as a parallel trial. A run-in period of 2-8 weeks was followed by randomization. Children were randomized in two processes: the first determined the crossover sequence of asthma therapy and the second determined the blinded antipyretic/analgesic medication to be used as needed for fever or pain throughout the 48 week duration of the crossover study, with stratification by clinical center. The three 16-week treatment periods of the INFANT study included: daily ICS (fluticasone propionate, two inhalations, 44 μg each, twice daily), daily LTRA (montelukast, 4 mg, once daily at bedtime), and as-needed ICS co-administered with a short-acting bronchodilator for symptom relief (fluticasone propionate, two inhalations, 44 μg each; albuterol sulfate, two inhalations, 90 μg each). The two antipyretic/analgesic medications used in AVICA were acetaminophen (160 mg per 5ml, administered every 6 hours as needed) and ibuprofen (100 mg per 5ml, administered every 6 hours as needed).

During the run-in period, eligible children received one oral medication and one inhaled medication for daily use, open-label albuterol sulfate and open-label prednisolone. The run-in duration was variable and based upon whether the child was currently receiving step 2 therapy or if the child qualified based on exacerbation history. Children were ineligible for randomization if any of the following were observed during the run-in period: completion of <75% of daily electronic diaries, an exacerbation requiring systemic corticosteroids, daily asthma symptoms if not receiving active therapy, or asthma symptoms >2 days per week if receiving active therapy.

For the INFANT trial, caregivers recorded symptoms, healthcare utilization and medication use in electronic diaries each day at bedtime. To account for transitioning from one treatment group to another, the data collected during the first two weeks of each period were not included in the analysis of asthma control days (ACDs). Days with missing diary data were also excluded from ACD determination. Treatment period failure was achieved if a child experienced two exacerbations, separated by at least one week, in a single 16-week treatment period. When two exacerbations occurred, the child was advanced to the next treatment period. Study failure was achieved if the participant: received four courses of prednisolone after randomization, was hospitalized >24 hours for an acute asthma exacerbation, or was moved forward to the next treatment period two times during the course of the study.

Phenotyping with aeroallergen sensitization and blood eosinophils was performed in the INFANT study. Peripheral blood eosinophil counts were determined from one aliquot of whole blood by an automated assay at each clinical site. Eosinophil cationic protein (ECP), total serum immunoglobulin E (IgE) and specific IgE concentrations were quantified by a commercial laboratory. Specific IgE was performed for a nationally representative panel of inhalant aeroallergens. Aeroallergen test results were considered positive if values were ≥ 0.35 kU/L. Urinary leukotriene E4 (LTE4) concentrations were measured by mass spectrometry as previously described and were expressed per mg of creatinine.

For the AVICA trial, caregivers reported medication use at each assessment point. Diaries and questionnaires were used to track the timing and reasons for the use of the trial medication. Because acetaminophen and ibuprofen are widely available over the counter, open-label administration of these medications was assessed every 4 weeks.

The primary outcome for the INFANT trial was the differential response to three therapies on the basis of fixed threshold criteria for the following asthma control measures, which encompassed domains of risk and impairment: the time from the start of the treatment period to an asthma exacerbation treated with systemic corticosteroids, and the annualized number of ACDs from within that period. Children were defined as differential responders if the time to an asthma exacerbation was at least four weeks longer, or if the number of annualized ACDs was at least 31 days more for one treatment than another. The primary outcome for the AVICA trial was the number of asthma exacerbations per participant.

Conclusions

The INFANT study found clinically relevant improvements in response to one treatment versus others in the majority of young children with mild persistent asthma symptoms and recurrent wheezing episodes. This study also found that phenotyping can be used to predict the medication strategy associated with the best response.

Fitzpatrick AM, Jackson DJ, Mauger DT, et al. Individualized therapy for persistent asthma in young children. J Allergy Clin Immunol. 2016;138(6):1608–1618.e12. doi:10.1016/j.jaci.2016.09.028

The AVICA study found that as-needed use of acetaminophen resulted in no significant difference in the frequency of asthma exacerbations as compared to as-needed use of ibuprofen among young children with mild persistent asthma.

Sheehan WJ, Mauger DT, Paul IM, et al. Acetaminophen versus Ibuprofen in Young Children with Mild Persistent Asthma. N Engl J Med. 2016;375(7):619–630. doi:10.1056/NEJMoa1515990

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