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

Primary Purpose

Asthma

Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Budesonide
Placebo Budesonide
Sponsored by
Milton S. Hershey Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Asthma

Eligibility Criteria

12 Months - 53 Months (Child)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • University of Arizona College of Medicine
  • Kaiser Permanente Medical Center
  • National Jewish Medical and Research Center
  • Washington University School of Medicine
  • University of Wisconsin - Madison

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Placebo Budesonide

Budesonide

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Rate of Exacerbations Requiring Systemic Corticosteroids
The rate of exacerbations was calculated as the number of exacerbations requiring prednisone per years of follow-up

Secondary Outcome Measures

Proportion of Episode-free Days
An episode-free day consisted of no asthma symptoms and no asthma rescue medications
Number of Urgent Care Visits, Emergency Department Visits, or Hospitalizations for Wheezing or Asthma Per 12 Months
Number of Participants With Treatment Failure
Treatment failure was defined as the occurrence of at least one of the following events: four courses of systemic corticosteroids one hospitalization for acute exacerbation of wheezing hypoxic seizure during an acute exacerbation of asthma/wheezing intubation for acute asthma/wheezing serious adverse event related to a study medication physician discretion with specific rationale
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
Change Between 12 Months and Baseline in Pulmonary Reactance and Resistance Measured Via Oscillometry
Adverse Events Associated With Corticosteroid Use
Number of Days of Absence From Daycare and Preschool for the Child and From Work for the Caregiver Per 12 Months
Proportion of Days With Rescue Albuterol Use
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
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

Full Information

First Posted
May 7, 2008
Last Updated
May 31, 2018
Sponsor
Milton S. Hershey Medical Center
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT00675584
Brief Title
CARE Network Maintenance Versus Intermittent Inhaled Steroids in Wheezing Toddlers (MIST)
Acronym
MIST
Official Title
Childhood Asthma Research and Education (CARE) Network Trial - Maintenance Versus Intermittent Inhaled Steroids in Wheezing Toddlers (MIST)
Study Type
Interventional

2. Study Status

Record Verification Date
May 2018
Overall Recruitment Status
Completed
Study Start Date
August 2008 (undefined)
Primary Completion Date
July 2010 (Actual)
Study Completion Date
July 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Milton S. Hershey Medical Center
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Asthma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
278 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Placebo Budesonide
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Budesonide
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Budesonide
Other Intervention Name(s)
Pulmicort Respules®
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo Budesonide
Other Intervention Name(s)
Placebo Pulmicort Respules®
Intervention Description
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.
Primary Outcome Measure Information:
Title
Rate of Exacerbations Requiring Systemic Corticosteroids
Description
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 Outcome Measure Information:
Title
Proportion of Episode-free Days
Description
An episode-free day consisted of no asthma symptoms and no asthma rescue medications
Time Frame
Measured during the 12-month follow-up period
Title
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
Title
Number of Participants With Treatment Failure
Description
Treatment failure was defined as the occurrence of at least one of the following events: four courses of systemic corticosteroids one hospitalization for acute exacerbation of wheezing hypoxic seizure during an acute exacerbation of asthma/wheezing intubation for acute asthma/wheezing serious adverse event related to a study medication physician discretion with specific rationale
Time Frame
Measured during the 12-month follow-up period
Title
Change Between 12 Months and Baseline in Exhaled Nitric Oxide (eNO)
Description
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
Title
Change Between 12 Months and Baseline in Pulmonary Reactance and Resistance Measured Via Oscillometry
Time Frame
baseline and 12 months
Title
Adverse Events Associated With Corticosteroid Use
Time Frame
Measured during the 12-month follow-up period
Title
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
Title
Proportion of Days With Rescue Albuterol Use
Time Frame
Measured during the 12-month follow-up period
Title
Change in Wheeze Severity During a Respiratory Tract Illness
Description
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
Title
Change Between 12 Months and Baseline in the Caregiver Quality-of-life
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Months
Maximum Age & Unit of Time
53 Months
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David T. Mauger, PhD
Organizational Affiliation
Penn State College of Medicine
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Stanley J. Szefler, MD, PhD
Organizational Affiliation
National Jewish Health
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Robert F. Lemanske, Jr., MD
Organizational Affiliation
University of Wisconsin, Madison
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Robert S. Zeiger, MD, PhD
Organizational Affiliation
Kaiser Permanente Medical Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Robert C. Strunk, MD
Organizational Affiliation
Washington University School of Medicine
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Fernando D. Martinez, MD
Organizational Affiliation
University of Arizona College of Medicine
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Lynn M. Taussig, MD
Organizational Affiliation
University of Denver
Official's Role
Study Chair
Facility Information:
Facility Name
University of Arizona College of Medicine
City
Tucson
State/Province
Arizona
ZIP/Postal Code
85724
Country
United States
Facility Name
Kaiser Permanente Medical Center
City
San Diego
State/Province
California
ZIP/Postal Code
92111
Country
United States
Facility Name
National Jewish Medical and Research Center
City
Denver
State/Province
Colorado
ZIP/Postal Code
80206
Country
United States
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
University of Wisconsin - Madison
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53792
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
22111718
Citation
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.
Results Reference
result
Links:
URL
http://www.asthma-carenet.org
Description
Click here for the Childhood Asthma Research and Education (CARE) Network Web site

Learn more about this trial

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

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