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

• ClinicalTrials.gov Identifier: NCT00675584
• Recruitment Status: Completed
• First Posted: May 9, 2008
• Results First Posted: June 1, 2012
• Last Update Posted: June 26, 2018
• Sponsor: Milton S. Hershey Medical Center
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): Vernon M. Chinchilli, PhD, Milton S. Hershey Medical Center

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Asthma
• Interventions: Drug: Budesonide; Drug: Placebo Budesonide
• Enrollment: 278

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Daily Budesonide	Intermittent Budesonide
Arm/Group 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.
Period Title: Overall Study
Started	139	139
Completed	100	113
Not Completed	39	26

Baseline Characteristics

Arm/Group Title		Daily Budesonide	Intermittent Budesonide	Total
Arm/Group 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.	Total of all reporting groups
Overall Number of Baseline Participants		139	139	278
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	139 participants	139 participants	278 participants
	<=18 years	139 100.0%	139 100.0%	278 100.0%
	Between 18 and 65 years	0 0.0%	0 0.0%	0 0.0%
	>=65 years	0 0.0%	0 0.0%	0 0.0%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	139 participants	139 participants	278 participants
		2.9 (0.9)	2.9 (0.9)	2.9 (0.9)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	139 participants	139 participants	278 participants
	Female	49 35.3%	37 26.6%	86 30.9%
	Male	90 64.7%	102 73.4%	192 69.1%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	139 participants	139 participants	278 participants
		139	139	278

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Even if a child terminated prior to completion of the 12 months of follow-up, he/she contributed to the numerator and denominator of the exacerbation rate

Arm/Group Title	Daily Budesonide	Intermittent Budesonide
Arm/Group 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.
Overall Number of Participants Analyzed	139	139
Mean (95% Confidence Interval); Unit of Measure: events per years of follow-up
	0.97; (0.76 to 1.22)	0.95; (0.75 to 1.20)

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Even if a child terminated prior to completion of the 12 months of follow-up, he/she contributed to the numerator and denominator of the proportion of episode-free days

Arm/Group Title	Daily Budesonide	Intermittent Budesonide
Arm/Group 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.
Overall Number of Participants Analyzed	139	139
Mean (95% Confidence Interval); Unit of Measure: proportion of episode-free days
	0.78; (0.76 to 0.81)	0.78; (0.75 to 0.80)

3. Secondary Outcome

Title	Number of Urgent Care Visits, Emergency Department Visits, or Hospitalizations for Wheezing or Asthma Per 12 Months
Description	[Not Specified]
Time Frame	Measured during the 12-month follow-up period

Outcome Measure Data

Analysis Population Description

Even if a child terminated prior to completion of the 12 months of follow-up, he/she contributed to the number of urgent care visits

Arm/Group Title	Daily Budesonide	Intermittent Budesonide
Arm/Group 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.
Overall Number of Participants Analyzed	139	139
Mean (95% Confidence Interval); Unit of Measure: visits per 12 months
	2.40; (1.91 to 3.02)	2.37; (1.89 to 2.97)

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Even if a child terminated prior to completion of the 12 months of follow-up, his/her data were included in the assessment of treatment failure

Arm/Group Title	Daily Budesonide	Intermittent Budesonide
Arm/Group 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.
Overall Number of Participants Analyzed	139	139
Measure Type: Count of Participants; Unit of Measure: Participants
	17 12.2%	9 6.5%

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Even if a child terminated prior to completion of the 12 months of follow-up, his/her data were included in the analysis based on the linear mixed-effects model

Arm/Group Title	Daily Budesonide	Intermittent Budesonide
Arm/Group 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.
Overall Number of Participants Analyzed	139	139
Least Squares Mean (95% Confidence Interval); Unit of Measure: parts per billion
	-0.14; (-0.32 to 0.04)	-0.18; (-0.38 to 0.02)

6. Secondary Outcome

Title	Change Between 12 Months and Baseline in Pulmonary Reactance and Resistance Measured Via Oscillometry
Description	[Not Specified]
Time Frame	baseline and 12 months

Outcome Measure Data

Analysis Population Description

Prior to enrollment of the first randomized study participant, the clinical investigators decided that it would be futile to perform oscillometry in children of the target age range for MIST (2-5 years of age). A previous CARE Network trial (PEAK) performed oscillometry in such children, but the data were highly variable and of poor quality.

Arm/Group Title	Daily Budesonide	Intermittent Budesonide
Arm/Group 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.
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

7. Secondary Outcome

Title	Adverse Events Associated With Corticosteroid Use
Description	[Not Specified]
Time Frame	Measured during the 12-month follow-up period

Outcome Measure Data

Analysis Population Description

All randomized children are included

Arm/Group Title	Daily Budesonide	Intermittent Budesonide
Arm/Group 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.
Overall Number of Participants Analyzed	139	139
Measure Type: Count of Participants; Unit of Measure: Participants
	3 2.2%	0 0.0%

8. Secondary Outcome

Title	Number of Days of Absence From Daycare and Preschool for the Child and From Work for the Caregiver Per 12 Months
Description	[Not Specified]
Time Frame	Measured during the 12-month follow-up period

Outcome Measure Data

Analysis Population Description

Even if a child terminated prior to completion of the 12 months of follow-up, he/she contributed to the number of days

Arm/Group Title	Daily Budesonide	Intermittent Budesonide
Arm/Group 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.
Overall Number of Participants Analyzed	139	139
Mean (95% Confidence Interval); Unit of Measure: days per 12 months
	3.02; (2.22 to 4.12)	2.72; (2.00 to 3.70)

9. Secondary Outcome

Title	Proportion of Days With Rescue Albuterol Use
Description	[Not Specified]
Time Frame	Measured during the 12-month follow-up period

Outcome Measure Data

Analysis Population Description

Even if a child terminated prior to completion of the 12 months of follow-up, he/she contributed to the number of days

Arm/Group Title	Daily Budesonide	Intermittent Budesonide
Arm/Group 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.
Overall Number of Participants Analyzed	139	139
Mean (95% Confidence Interval); Unit of Measure: proportion of days
	0.05; (0.04 to 0.06)	0.06; (0.05 to 0.07)

10. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The data from every respiratory tract illness is included in the analysis

Arm/Group Title	Daily Budesonide	Intermittent Budesonide
Arm/Group 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.
Overall Number of Participants Analyzed	139	139
Mean (95% Confidence Interval); Unit of Measure: units on a scale
	0.5; (0.1 to 0.8)	0.8; (0.5 to 1.1)

11. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Even if a child terminated prior to completion of the 12 months of follow-up, his/her data were included in the analysis based on the linear mixed-effects model

Arm/Group Title	Daily Budesonide	Intermittent Budesonide
Arm/Group 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.
Overall Number of Participants Analyzed	139	139
Least Squares Mean (95% Confidence Interval); Unit of Measure: units on a scale
	1.4; (-3.0 to 5.8)	2.0; (-1.8 to 5.8)

Adverse Events

Time Frame	1 year
Adverse Event Reporting Description	does not differ from the clinicaltrials.gov definitions
Arm/Group Title	Daily Budesonide		Intermittent Budesonide
Arm/Group 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.
All-Cause Mortality
	Daily Budesonide		Intermittent Budesonide
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	Daily Budesonide		Intermittent Budesonide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/139 (5.04%)		10/139 (7.19%)
Injury, poisoning and procedural complications
other †	3/139 (2.16%)	3	5/139 (3.60%)	5
Respiratory, thoracic and mediastinal disorders
hospitalization due to exacerbation †	4/139 (2.88%)	4	5/139 (3.60%)	5
† Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Daily Budesonide		Intermittent Budesonide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/139 (6.47%)		11/139 (7.91%)
Gastrointestinal disorders
nausea or vomiting *	9/139 (6.47%)	9	11/139 (7.91%)	11
* Indicates events were collected by non-systematic assessment

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.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Vernon M. Chinchilli, PhD
• Organization: Penn State Hershey College of Medicine
• Phone: 717-531-4262
• EMail: vchinchi@psu.edu

Publications of Results:

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.

• Responsible Party: Vernon M. Chinchilli, PhD, Milton S. Hershey Medical Center
• ClinicalTrials.gov Identifier: NCT00675584
• Other Study ID Numbers: 581; 5U10HL064313 ( U.S. NIH Grant/Contract ); 5U10HL064288 ( U.S. NIH Grant/Contract ); 5U10HL064305 ( U.S. NIH Grant/Contract ); 5U10HL064295 ( U.S. NIH Grant/Contract ); 5U10HL064287 ( U.S. NIH Grant/Contract ); 5U10HL064307 ( U.S. NIH Grant/Contract )
• First Submitted: May 7, 2008
• First Posted: May 9, 2008
• Results First Submitted: April 30, 2012
• Results First Posted: June 1, 2012
• Last Update Posted: June 26, 2018