Childhood Asthma Research and Education (CARE) Network Trial – Maintenance Versus Intermittent Inhaled Steroids in Wheezing Toddlers (MIST)
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August 2008 – July 2010
February 24, 2021
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The CARE-MIST study aimed to determine whether a daily low-dose regimen of budesonide would be superior to an intermittent high-dose regimen in young children who had positive values on the modified asthma predictive index, along with recurrent wheezing, high-risk asthma, and low impairment.
Recurrent wheezing episodes in pre-school-age children are usually triggered by respiratory tract infections, which often progress to severe exacerbations requiring systemic glucocorticoids and frequent use of health care services. In children under the age of 5 years who had at least four wheezing episodes during the previous year and positive values on the modified asthma predictive index (API) (indicating an increased likelihood of persistent asthma in the future), the National Asthma Education and Prevention Program Expert Panel Report 3 (EPR-3) recommends the initiation of long-term daily inhaled glucocorticoid therapy. Concern about growth retardation and parental resistance to a daily regimen of inhaled glucocorticoids for young children, who usually have only episodic but often severe symptoms, stimulated a search for alternative strategies. Therefore, the CARE-MIST study was initiated to investigate intermittent therapy with inhaled glucocorticoids in young children.
Eligible participants were children between the ages of 12 and 53 months, had at least four episodes of wheezing (or three episodes of wheezing and controller use for ≥3 months) during the previous year, had positive values on the modified API, and had at least one exacerbation requiring the use of systemic glucocorticoids, urgent or emergency care, or hospitalization. Children were excluded from the study if they had received more than six courses of oral glucocorticoids or had been hospitalized more than two times for wheezing during the previous year.
450 children were enrolled with 278 children undergoing randomization. 139 were randomized to the intermittent-regimen group and 139 to the daily-regimen group. 213 children completed the study.
CARE-MIST was a randomized, double-blind, parallel-group trial. The study was conducted at seven sites. During a 2-week run-in period, all patients received nightly placebo doses of budesonide inhalation suspension and as-needed albuterol. If during the 2-week run-in period the child had fewer than 3 days per week of albuterol use and fewer than 2 nights with awakening, then the child underwent randomization. The run-in period was followed by a 52-week treatment period. In the intermittent-regimen group, high-dose nebulized budesonide inhalation suspension was administered at a dose of 1 mg twice daily for 7 days at the onset of a predefined respiratory tract illness. A matched placebo was administered once nightly on all other days. In the daily-regimen group, daily low-dose nebulized budesonide inhalation suspension was administered at a dose of 0.5 mg once nightly. During respiratory tract illnesses, an appropriately matched morning placebo was used for 7 days. To maintain blinding during respiratory tract illnesses, daily treatments were discontinued for 7 days and respiratory illness kits that were based on the study-group assignment were administered for 7 days. After 7 days, regular daily treatments were restarted.
Open-label albuterol was administered per protocol during a respiratory tract illness and as needed. Albuterol was administered by inhalation at a dose of 180 mcg per treatment or by nebulization with a 2.5 mg albuterol solution per treatment. Oral glucocorticosteroids (prednisolone) were available for all children at home and were started after physician consultation (telephone or in-person) based upon a specific published protocol.
In daily diaries, parents reported symptoms with the severity of each scored from 0 to 5 (higher scores indicating greater severity), medications, health care visits, and absences from day care or preschool. Clinic visits were scheduled four weeks following randomization, and then every eight weeks. Telephone calls were scheduled two weeks following randomization, followed by calls four weeks after each scheduled clinic visit. The Infant Toddler Quality of Life validated questionnaire was performed at specified visits during the trial. Fractional exhaled nitric oxide (FENO) measurements were obtained from subjects 4 times during the course of the study. Nasal secretions were collected by direct “nasal blow technique” or nasal swab at randomization, visit 5 and during each respiratory-tract illness at home by a trained parent/guardian and analyzed for the presence of respiratory viruses.
The primary outcome measure was the frequency of exacerbations, which was defined as the number of courses of an oral glucocorticoid (prednisolone) started for acute wheezing after consultation with a physician (by telephone or in person) on the basis of a specific published protocol during the 12-month treatment period.
A daily low-dose regimen of budesonide inhalation suspension was not superior to an intermittent high-dose regimen, administered for 7 days during a predefined respiratory tract illness, with respect to the frequency of exacerbations in preschool-age children at risk for asthma and future exacerbations.
Zeiger RS, Mauger D, Bacharier LB, et al. Daily or intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med. 2011;365(21):1990-2001. doi:10.1056/NEJMoa1104647
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