Asthma
Conditions
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.
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.
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.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Milton S. Hershey Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Months to 53 Months
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Exacerbations Requiring Systemic Corticosteroids | Measured during the 12-month follow-up period | The rate of exacerbations was calculated as the number of exacerbations requiring prednisone per years of follow-up |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Urgent Care Visits, Emergency Department Visits, or Hospitalizations for Wheezing or Asthma Per 12 Months | Measured during the 12-month follow-up period | — |
| Number of Participants With Treatment Failure | Measured during the 12-month follow-up period | 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 |
| Change Between 12 Months and Baseline in Exhaled Nitric Oxide (eNO) | baseline and 12 months | 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 | baseline and 12 months | — |
| Proportion of Episode-free Days | Measured during the 12-month follow-up period | An episode-free day consisted of no asthma symptoms and no asthma rescue medications |
| Number of Days of Absence From Daycare and Preschool for the Child and From Work for the Caregiver Per 12 Months | Measured during the 12-month follow-up period | — |
| Proportion of Days With Rescue Albuterol Use | Measured during the 12-month follow-up period | — |
| Change in Wheeze Severity During a Respiratory Tract Illness | Measured during the first seven days for each 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 | baseline and 12 months | 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 |
| Adverse Events Associated With Corticosteroid Use | Measured during the 12-month follow-up period | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Daily 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. | 139 |
| Intermittent 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. | 139 |
| Total | 278 |
Baseline characteristics
| Characteristic | Intermittent Budesonide | Daily Budesonide | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 139 Participants | 139 Participants | 278 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 2.9 years STANDARD_DEVIATION 0.9 | 2.9 years STANDARD_DEVIATION 0.9 | 2.9 years STANDARD_DEVIATION 0.9 |
| Region of Enrollment United States | 139 participants | 139 participants | 278 participants |
| Sex: Female, Male Female | 37 Participants | 49 Participants | 86 Participants |
| Sex: Female, Male Male | 102 Participants | 90 Participants | 192 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 139 | 11 / 139 |
| serious Total, serious adverse events | 7 / 139 | 10 / 139 |
Outcome results
Primary
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
Population: 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 | Measure | Value (MEAN) |
|---|---|---|
| Daily Budesonide | Rate of Exacerbations Requiring Systemic Corticosteroids | 0.97 events per years of follow-up |
| Intermittent Budesonide | Rate of Exacerbations Requiring Systemic Corticosteroids | 0.95 events per years of follow-up |
Secondary
Adverse Events Associated With Corticosteroid Use
Time frame: Measured during the 12-month follow-up period
Population: All randomized children are included
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Daily Budesonide | Adverse Events Associated With Corticosteroid Use | 3 Participants |
| Intermittent Budesonide | Adverse Events Associated With Corticosteroid Use | 0 Participants |
Secondary
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Daily Budesonide | Change Between 12 Months and Baseline in Exhaled Nitric Oxide (eNO) | -0.14 parts per billion |
| Intermittent Budesonide | Change Between 12 Months and Baseline in Exhaled Nitric Oxide (eNO) | -0.18 parts per billion |
Secondary
Change Between 12 Months and Baseline in Pulmonary Reactance and Resistance Measured Via Oscillometry
Time frame: baseline and 12 months
Population: 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.
Secondary
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
Population: 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 | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Daily Budesonide | Change Between 12 Months and Baseline in the Caregiver Quality-of-life | 1.4 units on a scale |
| Intermittent Budesonide | Change Between 12 Months and Baseline in the Caregiver Quality-of-life | 2.0 units on a scale |
Secondary
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
Population: The data from every respiratory tract illness is included in the analysis
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Daily Budesonide | Change in Wheeze Severity During a Respiratory Tract Illness | 0.5 units on a scale |
| Intermittent Budesonide | Change in Wheeze Severity During a Respiratory Tract Illness | 0.8 units on a scale |
Secondary
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
Population: Even if a child terminated prior to completion of the 12 months of follow-up, he/she contributed to the number of days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Daily Budesonide | Number of Days of Absence From Daycare and Preschool for the Child and From Work for the Caregiver Per 12 Months | 3.02 days per 12 months |
| Intermittent Budesonide | Number of Days of Absence From Daycare and Preschool for the Child and From Work for the Caregiver Per 12 Months | 2.72 days per 12 months |
Secondary
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
Population: 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 | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Daily Budesonide | Number of Participants With Treatment Failure | 17 Participants |
| Intermittent Budesonide | Number of Participants With Treatment Failure | 9 Participants |
Secondary
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
Population: 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 | Measure | Value (MEAN) |
|---|---|---|
| Daily Budesonide | Number of Urgent Care Visits, Emergency Department Visits, or Hospitalizations for Wheezing or Asthma Per 12 Months | 2.40 visits per 12 months |
| Intermittent Budesonide | Number of Urgent Care Visits, Emergency Department Visits, or Hospitalizations for Wheezing or Asthma Per 12 Months | 2.37 visits per 12 months |
Secondary
Proportion of Days With Rescue Albuterol Use
Time frame: Measured during the 12-month follow-up period
Population: Even if a child terminated prior to completion of the 12 months of follow-up, he/she contributed to the number of days
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Daily Budesonide | Proportion of Days With Rescue Albuterol Use | 0.05 proportion of days |
| Intermittent Budesonide | Proportion of Days With Rescue Albuterol Use | 0.06 proportion of days |
Secondary
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
Population: 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 | Measure | Value (MEAN) |
|---|---|---|
| Daily Budesonide | Proportion of Episode-free Days | 0.78 proportion of episode-free days |
| Intermittent Budesonide | Proportion of Episode-free Days | 0.78 proportion of episode-free days |