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CompletedNCT00675584MISTUpdated Jun 26, 2018Results posted

CARE Network Maintenance Versus Intermittent Inhaled Steroids in Wheezing Toddlers (MIST)

A Phase 3 interventional study of Budesonide and Placebo Budesonide in Asthma, sponsored by Milton S. Hershey Medical Center. Completed at 5 sites in United States. Open to participants aged 12 Months to 53 Months. Per ClinicalTrials.gov, last updated 2018-06-26.

Sponsored by Milton S. Hershey Medical Center · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
278
Allocation
Randomized
Ages
12 Months to 53 Months
Sex
All
01

Study summary

Asthma affects about 4 million children in the United States and is a leading cause of hospitalizations and school absenteeism. Continuous wheezing in very young children may develop into asthma. Low doses of inhaled corticosteroids (ICS) are commonly prescribed to treat children with particularly bad wheezing episodes. This study will compare the safety and effectiveness of low doses of ICS taken daily versus higher doses of ICS taken only during respiratory tract illnesses for toddlers with continuous wheezing or coughing illnesses.

Read the detailed description

Childhood asthma can be caused by many factors, including allergens, cigarette smoke, air pollution, or infections. Symptoms include wheezing, shortness of breath, chest tightness, and coughing. Wheezing illnesses are common during the first several years of life, and continuous wheezing, or recurrent intermittent wheezing, may be an indicator of asthma. Recurrent intermittent wheezing can also lead to breathing difficulties, sleep disturbances, and severe exacerbations that result in emergency department visits, hospitalizations, or even death. The Prevention of Early Asthma in Kids (PEAK) and Acute Intervention Management Strategies (AIMS) studies, both of which are part of the Childhood Asthma Research and Education (CARE) Network, as well as several other studies, have identified therapies that may improve recurrent wheezing in young children. This study will compare the safety and effectiveness of two treatment regimens-low doses of ICS taken on a daily basis versus higher doses of ICS taken only during respiratory tract illnesses-at improving recurrent wheezing in toddlers. Study researchers will also identify individual characteristics (e.g., age, gender, family history of asthma and allergies, the degree of allergy, genetics) that may be associated with treatment response. Lastly, the relationship of virus infections to respiratory illnesses, wheezing episodes, and response to study treatments will also be studied.

This study will enroll children between 12 and 53 months of age who have experienced episodes of wheezing or coughing in the year before study entry, with at least one episode that required one of the following: oral steroids, an urgent unscheduled medical visit, an emergency room visit, or hospitalization. This study will begin with a 2-week evaluation period during which potential participants will receive placebo once a day. Parents will document their child's asthma symptoms and medication use in a daily diary. Next, at a baseline study visit, eligible participants will be randomly assigned to one of the following two 12-month treatment groups:

  • Group 1 participants will receive a low dose of ICS once a day at night, except during respiratory tract illnesses. During a respiratory tract illness, participants will receive placebo each morning and a low dose of ICS each night for 7 days.
  • Group 2 participants will receive a high dose of ICS twice a day for 7 days during each respiratory illness and placebo once a day at night at all other times.

Throughout the 12 months of treatment, all participants will receive albuterol to treat respiratory symptoms and prednisolone if asthma symptoms worsen. Parents will be given an action plan to help manage their child's symptoms, and during respiratory illnesses, parents will contact study researchers to determine the best treatment plan. Study visits will occur at baseline and Weeks 4, 12, 20, 28, 36, 44, and 52. Participants' parents will take part in scheduled telephone interviews one month after each clinic visit to provide information on their child's asthma symptoms, study medication use, and health problems. Most study visits will include a physical exam and lung function testing. At select study visits, the following will occur: allergy skin testing, blood collection, nasal mucus sampling, and parent questionnaires to assess asthma, quality of life, and environmental factors. A portion of the participants' blood will undergo genetic analysis; a blood collection from parents for genetic analysis will be optional. Throughout the treatment period, participants' parents will record asthma symptoms and medication usage in a daily diary.

02

Conditions studied

  • Asthma

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03

In context

Asthma

4,010 studies on the registry are indexed under Asthma; 514 are open to participants now.

This study's enrollment of 278 is above the median of 83 across 2,814 interventional studies indexed under Asthma.

Browse Asthma studies →

Lead sponsor

Milton S. Hershey Medical Center is the lead sponsor of 491 studies on the registry; 59 are open to participants now.

Of its 58 completed or terminated interventional studies of FDA-regulated products, 44 (76%) have results posted.

Browse Milton S. Hershey Medical Center studies →

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
12 Months to 53 Months
Sexes eligible
All
Accepts healthy volunteers
No

Eligibility criteria

Inclusion Criteria at Screening Visit:

Participants who meet all of the following criteria are eligible for study entry. Participants may be reassessed if not initially eligible.

  • Positive asthma predictive index (API) status
  • A history of at least 4 wheezing episodes in the prior year with at least one physician diagnosed or at least 3 wheezing episodes in the prior year with at least one physician diagnosed and at least 3 months of asthma controller therapy in the prior year
  • Experienced a severe exacerbation requiring systemic corticosteroids, urgent unscheduled or emergency visit, or hospitalization in the 12 months before the screening visit
  • All immunizations must be completed, including varicella (unless the child has already had clinical varicella). If the child needs the varicella vaccine, this will be arranged with the primary care physician and must be received before study entry.
  • Allows blood to be used for genetic analysis
  • Willingness to provide informed consent by the child's parent or guardian

Exclusion Criteria at Screening Visit:

Participants who meet any of the following criteria are NOT eligible for enrollment, but they may be re-enrolled if these exclusion criteria disappear:

  • Use of more than six courses of systemic corticosteroids in the 12 months before the screening visit
  • More than two hospitalizations for wheezing illnesses in the 12 months before the screening visit
  • Use of oral or systemic corticosteroids in the 2 weeks before the screening visit
  • Current treatment with antibiotics for diagnosed sinus disease
  • Current participation or has participated in the month before the screening visit in another investigational drug trial
  • Evidence that the family may be unreliable or nonadherent, or may move from the clinical center area before trial completion
  • Medically unable to use systemic corticosteroids
  • Clinically relevant gastroesophageal reflux
  • Inability of the child to cooperate with nebulizer therapy

Participants who meet any of the following criteria are NOT eligible for enrollment, and they may not be re-enrolled:

  • Gestation less than late preterm, as defined as birth before 34 weeks gestational age
  • Significant developmental delay/failure to thrive, defined as crossing of two major percentile lines during the last year for age and gender. If a child plots less than the 10th percentile for age and gender, a growth chart for the previous year will be obtained from the child's primary care provider.
  • Head circumference less than the 3rd percentile or greater than the 97th percentile unless medical evaluation documents no associated illness
  • Presence of lung disease other than asthma, such as cystic fibrosis and bronchopulmonary dysplasia (BPD). Evaluation during the screening process will assure that an adequate evaluation of other lung diseases has been performed.
  • Presence of other significant medical illnesses (e.g., cardiac, liver, gastrointestinal, endocrine) that would place the child at increased risk of participating in the study
  • Immunodeficiency disorders
  • History of respiratory failure requiring mechanical ventilation
  • History of hypoxic seizure
  • History of significant adverse reaction to any study medication ingredient

Exclusion Criteria at Baseline Visit:

Participants will be ineligible to continue in the study and be randomly assigned to a treatment group if any of the following is documented during the 2-week observation period, but they may be re-enrolled if these exclusion criteria disappear:

  • Persistent symptomatic asthma, as defined as experiencing symptoms requiring albuterol use on average three or more days per week or two or more night time awakenings due to asthma-associated symptoms
  • Inadequate adherence (less than 75% of days) to diary card completion or nebulizer medication use
  • Use of any asthma medication except albuterol (used on as needed basis)
05

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
278 participants (actual)

Study arms

  • Active comparator
    Placebo Budesonide

    Participants will receive 0.5 mg of ICS (budesonide as Pulmicort Respules®) once a day at night, except during respiratory tract illnesses. During respiratory tract illnesses, participants will receive placebo each morning and 0.5 mg of budesonide each night for 7 days.

    Drug: Budesonide · Drug: Placebo Budesonide

  • Experimental
    Budesonide

    Participants will receive 1 mg of ICS (budesonide as Pulmicort Respules®) twice a day for 7 days at the onset of a respiratory tract illness; they will receive placebo ICS once a day at all other times during the study.

    Drug: Budesonide · Drug: Placebo Budesonide

Interventions

  • DrugBudesonide

    Participants in Arm 1 will receive 0.5 mg of budesonide once a day. Participants in Arm 2 will receive 1 mg of budesonide twice a day for 7 days at the onset of respiratory tract illnesses.

    Also known as: Pulmicort Respules®

  • DrugPlacebo Budesonide

    Participants in Arm 1 will receive placebo budesonide each morning during respiratory tract illnesses for 7 days. Participants in Arm 2 will receive placebo budesonide once a day for the entire study, other than when they have a respiratory tract illness.

    Also known as: Placebo Pulmicort Respules®

06

What researchers measure

Primary outcomes

  1. Rate of Exacerbations Requiring Systemic Corticosteroids

    The rate of exacerbations was calculated as the number of exacerbations requiring prednisone per years of follow-up

    Time frame: Measured during the 12-month follow-up period

Secondary outcomes

  1. Proportion of Episode-free Days

    An episode-free day consisted of no asthma symptoms and no asthma rescue medications

    Time frame: Measured during the 12-month follow-up period

  2. Number of Urgent Care Visits, Emergency Department Visits, or Hospitalizations for Wheezing or Asthma Per 12 Months

    Time frame: Measured during the 12-month follow-up period

  3. Number of Participants With Treatment Failure

    Treatment failure was defined as the occurrence of at least one of the following events: 1. four courses of systemic corticosteroids 2. one hospitalization for acute exacerbation of wheezing 3. hypoxic seizure during an acute exacerbation of asthma/wheezing 4. intubation for acute asthma/wheezing 5. serious adverse event related to a study medication 6. physician discretion with specific rationale

    Time frame: Measured during the 12-month follow-up period

  4. Change Between 12 Months and Baseline in Exhaled Nitric Oxide (eNO)

    Exhaled nitric oxide (eNO) is measured in parts per billion, and the change constructed between 12 months and baseline

    Time frame: baseline and 12 months

  5. Change Between 12 Months and Baseline in Pulmonary Reactance and Resistance Measured Via Oscillometry

    Time frame: baseline and 12 months

  6. Adverse Events Associated With Corticosteroid Use

    Time frame: Measured during the 12-month follow-up period

  7. Number of Days of Absence From Daycare and Preschool for the Child and From Work for the Caregiver Per 12 Months

    Time frame: Measured during the 12-month follow-up period

  8. Proportion of Days With Rescue Albuterol Use

    Time frame: Measured during the 12-month follow-up period

  9. Change in Wheeze Severity During a Respiratory Tract Illness

    Wheeze severity is scored as 0 (none) to 5 (very severe) during a respiratory tract illness

    Time frame: Measured during the first seven days for each respiratory tract illness

  10. Change Between 12 Months and Baseline in the Caregiver Quality-of-life

    The caregiver quality-of-life questionnaire consists of seven questions, each scored from 0 (worse) to 3 (best), and all seven questions are summed to yield a total score ranging from 0 to 21

    Time frame: baseline and 12 months

07

Results

Posted Jun 1, 2012
Limitations and caveats
May not be applicable to young children whose asthma is more severe than that of the children in the study. Daily or intermittent use of inhaled glucocorticoids may not be efficacious in preschool-age children with transient or infrequent wheezing.

Participant flow

Participant flow — Overall Study
MilestoneDaily BudesonideIntermittent Budesonide
Started139139
Completed100113
Not completed3926

Outcome measures

PrimaryRate of Exacerbations Requiring Systemic Corticosteroids

The rate of exacerbations was calculated as the number of exacerbations requiring prednisone per years of follow-up

Time frame:
Measured during the 12-month follow-up period
Reported as:
Mean · events per years of follow-up
Rate of Exacerbations Requiring Systemic Corticosteroids
events per years of follow-upDaily BudesonideIntermittent Budesonide
Rate of Exacerbations Requiring Systemic Corticosteroids0.97 (0.76 to 1.22)0.95 (0.75 to 1.20)
SecondaryProportion of Episode-free Days

An episode-free day consisted of no asthma symptoms and no asthma rescue medications

Time frame:
Measured during the 12-month follow-up period
Reported as:
Mean · proportion of episode-free days
Proportion of Episode-free Days
proportion of episode-free daysDaily BudesonideIntermittent Budesonide
Proportion of Episode-free Days0.78 (0.76 to 0.81)0.78 (0.75 to 0.80)
SecondaryNumber of Urgent Care Visits, Emergency Department Visits, or Hospitalizations for Wheezing or Asthma Per 12 Months
Time frame:
Measured during the 12-month follow-up period
Reported as:
Mean · visits per 12 months
Number of Urgent Care Visits, Emergency Department Visits, or Hospitalizations for Wheezing or Asthma Per 12 Months
visits per 12 monthsDaily BudesonideIntermittent Budesonide
Number of Urgent Care Visits, Emergency Department Visits, or Hospitalizations for Wheezing or Asthma Per 12 Months2.40 (1.91 to 3.02)2.37 (1.89 to 2.97)
SecondaryNumber of Participants With Treatment Failure

Treatment failure was defined as the occurrence of at least one of the following events: 1. four courses of systemic corticosteroids 2. one hospitalization for acute exacerbation of wheezing 3. hypoxic seizure during an acute exacerbation of asthma/wheezing 4. intubation for acute asthma/wheezing 5. serious adverse event related to a study medication 6. physician discretion with specific rationale

Time frame:
Measured during the 12-month follow-up period
Reported as:
Count of participants · Participants
Number of Participants With Treatment Failure
ParticipantsDaily BudesonideIntermittent Budesonide
Number of Participants With Treatment Failure179
SecondaryChange Between 12 Months and Baseline in Exhaled Nitric Oxide (eNO)

Exhaled nitric oxide (eNO) is measured in parts per billion, and the change constructed between 12 months and baseline

Time frame:
baseline and 12 months
Reported as:
Least squares mean · parts per billion
Change Between 12 Months and Baseline in Exhaled Nitric Oxide (eNO)
parts per billionDaily BudesonideIntermittent Budesonide
Change Between 12 Months and Baseline in Exhaled Nitric Oxide (eNO)-0.14 (-0.32 to 0.04)-0.18 (-0.38 to 0.02)
SecondaryChange Between 12 Months and Baseline in Pulmonary Reactance and Resistance Measured Via Oscillometry
Time frame:
baseline and 12 months

No measurements were reported for this outcome.

SecondaryAdverse Events Associated With Corticosteroid Use
Time frame:
Measured during the 12-month follow-up period
Reported as:
Count of participants · Participants
Adverse Events Associated With Corticosteroid Use
ParticipantsDaily BudesonideIntermittent Budesonide
Adverse Events Associated With Corticosteroid Use30
SecondaryNumber of Days of Absence From Daycare and Preschool for the Child and From Work for the Caregiver Per 12 Months
Time frame:
Measured during the 12-month follow-up period
Reported as:
Mean · days per 12 months
Number of Days of Absence From Daycare and Preschool for the Child and From Work for the Caregiver Per 12 Months
days per 12 monthsDaily BudesonideIntermittent Budesonide
Number of Days of Absence From Daycare and Preschool for the Child and From Work for the Caregiver Per 12 Months3.02 (2.22 to 4.12)2.72 (2.00 to 3.70)
SecondaryProportion of Days With Rescue Albuterol Use
Time frame:
Measured during the 12-month follow-up period
Reported as:
Mean · proportion of days
Proportion of Days With Rescue Albuterol Use
proportion of daysDaily BudesonideIntermittent Budesonide
Proportion of Days With Rescue Albuterol Use0.05 (0.04 to 0.06)0.06 (0.05 to 0.07)
SecondaryChange in Wheeze Severity During a Respiratory Tract Illness

Wheeze severity is scored as 0 (none) to 5 (very severe) during a respiratory tract illness

Time frame:
Measured during the first seven days for each respiratory tract illness
Reported as:
Mean · units on a scale
Change in Wheeze Severity During a Respiratory Tract Illness
units on a scaleDaily BudesonideIntermittent Budesonide
Change in Wheeze Severity During a Respiratory Tract Illness0.5 (0.1 to 0.8)0.8 (0.5 to 1.1)
SecondaryChange Between 12 Months and Baseline in the Caregiver Quality-of-life

The caregiver quality-of-life questionnaire consists of seven questions, each scored from 0 (worse) to 3 (best), and all seven questions are summed to yield a total score ranging from 0 to 21

Time frame:
baseline and 12 months
Reported as:
Least squares mean · units on a scale
Change Between 12 Months and Baseline in the Caregiver Quality-of-life
units on a scaleDaily BudesonideIntermittent Budesonide
Change Between 12 Months and Baseline in the Caregiver Quality-of-life1.4 (-3.0 to 5.8)2.0 (-1.8 to 5.8)

Adverse events

Collected over 1 year. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Daily Budesonide—7/139 (5%)9/139 (6.5%)
Intermittent Budesonide—10/139 (7.2%)11/139 (7.9%)
Most frequent serious events
Most frequent serious events
EventDaily BudesonideIntermittent Budesonide
hospitalization due to exacerbationRespiratory, thoracic and mediastinal disorders4/1395/139
otherInjury, poisoning and procedural complications3/1395/139
Most frequent other events
Most frequent other events
EventDaily BudesonideIntermittent Budesonide
nausea or vomitingGastrointestinal disorders9/13911/139

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)Daily BudesonideIntermittent BudesonideTotal
<=18 years139139278
Between 18 and 65 years000
>=65 years000
Age, Continuous
Age, Continuous(years)Daily BudesonideIntermittent BudesonideTotal
Mean2.9 ± 0.92.9 ± 0.92.9 ± 0.9
Sex: Female, Male
Sex: Female, Male(Participants)Daily BudesonideIntermittent BudesonideTotal
Female493786
Male90102192
Region of Enrollment
Region of Enrollment(participants)Daily BudesonideIntermittent BudesonideTotal
United States139139278
08

Study locations

5 sites
  • University of Arizona College of Medicine
    Tucson, Arizona 85724, United States
  • Kaiser Permanente Medical Center
    San Diego, California 92111, United States
  • National Jewish Medical and Research Center
    Denver, Colorado 80206, United States
  • Washington University School of Medicine
    St Louis, Missouri 63110, United States
  • University of Wisconsin - Madison
    Madison, Wisconsin 53792, United States
09

References and documents

Publications

  • Zeiger RS, Mauger D, Bacharier LB, Guilbert TW, Martinez FD, Lemanske RF Jr, Strunk RC, Covar R, Szefler SJ, Boehmer S, Jackson DJ, Sorkness CA, Gern JE, Kelly HW, Friedman NJ, Mellon MH, Schatz M, Morgan WJ, Chinchilli VM, Raissy HH, Bade E, Malka-Rais J, Beigelman A, Taussig LM; CARE Network of the National Heart, Lung, and Blood Institute. Daily or intermittent budesonide in preschool children with recurrent wheezing. N Engl J Med. 2011 Nov 24;365(21):1990-2001. doi: 10.1056/NEJMoa1104647. PubMed 22111718 ↗
10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Jun 26, 2018, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT00675584
Lead sponsor
Milton S. Hershey Medical Center
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
Responsible party
Vernon M. Chinchilli, PhD (Professor and Chair, Department of Public Health Sciences, Milton S. Hershey Medical Center) — Principal investigator
First posted
May 9, 2008
Start date
Aug 2008
Primary completion
Jul 2010
Completion
Jul 2010
Results posted
Jun 1, 2012
Last update
Jun 26, 2018

Study contacts

David T. Mauger, PhD
principal investigator · Penn State College of Medicine
Stanley J. Szefler, MD, PhD
principal investigator · National Jewish Health
Robert F. Lemanske, Jr., MD
principal investigator · University of Wisconsin, Madison
Robert S. Zeiger, MD, PhD
principal investigator · Kaiser Permanente Medical Center
Robert C. Strunk, MD
principal investigator · Washington University School of Medicine
Fernando D. Martinez, MD
principal investigator · University of Arizona College of Medicine
Lynn M. Taussig, MD
study chair · University of Denver

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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