Respiratory Syncytial Virus, Bronchiolitis
Conditions
Brief summary
The main objective of the APW-RSV II clinical trial is to evaluate if the addition of azithromycin to routine bronchiolitis care, among infants hospitalized with RSV bronchiolitis, reduces the occurrence of recurrent wheeze during the preschool years.
Detailed description
The APW-RSV II clinical trial is a double blind, placebo-controlled, parallel-group, randomized trial, including otherwise healthy 188 participants, ages 1-18 months, who are hospitalized due to RSV bronchiolitis. The study includes active treatment phase with azithromycin or placebo for 2 weeks, and an observational phase for up to 48 months. The main objective of the APW-RSV II clinical trial is to evaluate if the addition of azithromycin to routine bronchiolitis care, among infants hospitalized with RSV bronchiolitis, reduces the occurrence of recurrent wheeze (RW) during the preschool years. Study participants will be enrolled during 3 consecutive RSV seasons beginning in Fall 2016. Study participants will be randomized to receive PO azithromycin 10 mg/kg/day for 7 days followed by 5mg/kg/day for additional 7 days, or matched placebo. The primary clinical outcome is the time to the occurrence of a third episode of wheezing. The duration of follow up is 18-48 months, which is determined based on the year in which the participants is recruited: first year recruits will be followed for up to 48 months, while the 3rd year recruits will be followed for at least 18 months.
Interventions
Oral azithromycin 10mg/kg/day for 7 days; then oral azithromycin 5mg/kg/day for 7 additional days
DRUGPlacebo
Placebo suspension
Sponsors
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
1 Months to 18 Months
Healthy volunteers
No
Inclusion criteria
* Age: 1-18 months. * Hospitalization for the first episode of RSV bronchiolitis. * Confirmed RSV infection by positive nasal swab results (PCR assay and/or direct antigen detection). * At least two of the following symptoms/signs of bronchiolitis: respiratory rate greater than 40 breaths/minute; cough; wheezing; audible rales, crackles, and/or rhonchi; paradoxical chest movements (retractions)28. * Duration of respiratory symptoms from onset of symptoms of the current illness to admission is 120 hours (5 days) or less. * Randomization can be performed within 168 hours (7 days) from onset of symptoms. * Willingness to provide informed consent by the child's parent or guardian.
Exclusion criteria
* Prematurity (gestational age \< 36 weeks). * Presence or history of other significant disease (CNS, lung, cardiac, renal, GI, hepatic disease, hematologic, endocrine or immune disease). Children with atopic dermatitis and/or food allergy will not be excluded from the study. * Clinically significant gastroesophageal reflux currently treated with a daily anti-reflux medication (anti- H2 or PPI). * The child has significant developmental delay/failure to thrive, defined as weight \< 3% for age and gender. * History of previous (before the current episode) wheeze or previous (before the current episode) treatment with albuterol. * History of previous treatment with corticosteroid (systemic or inhaled) for respiratory issues. * Treatment (past or present) with montelukast. * Treatment with any macrolide antibiotic (azithromycin, clarithromycin or erythromycin) over the past 4 weeks or current treatment with any macrolide antibiotic. Current or prior treatment with non-macrolide antibiotic is not an exclusion criterion. * Chronic treatment with any daily medication other than vitamins or nutritional supplements. Although routine vitamin D supplement (400 IU per day) is not an exclusion criterion, high dose vitamin D supplements are not allowed. * Participation in another clinical trial. * Participant requires invasive mechanical ventilation due to RSV bronchiolitis. * Evidence that the family may be unreliable or non-adherent, or has definitive plans to move from the clinical center area before trial completion. * Contraindication of use of azithromycin or any other macrolide antibiotics such as history of allergic reaction (or other adverse reaction) to these antibiotics. * Diagnosis of asthma. * Treatment with other medication that may cause QT interval prolongation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced the Occurrence of a Third Episode of Post-RSV Wheezing (Recurrent Wheeze) | Follow up duration of 18-48 months | Episodes of wheezing were captured at each of the study telephone interviews and clinic visits using the question, Has your child's chest sounded wheezy or whistling (with and without a cold)?. A new wheezing episode was defined if at least 7 days without wheezing had been reported since the previous episode. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Number of Days With Respiratory Symptoms (Wheezing, Cough, or Shortness of Breath) | Follow up duration of 18-48 months | The number of days with respiratory symptoms were captured during clinic visits and by telephone interviews every other month using two questions, Does your child have coughing, wheezing, shortness of breath or chest tightness during the daytime?, If yes, estimate the number of days. We used a negative binomial regression analysis with an offset term to adjust for duration of follow-up to get the annualized rate estimate. |
| Annualized Number of Days With Albuterol Use | Follow up duration of 18-48 months | The number of days with albuterol use were captured during clinic visits and by telephone interviews every other month using two questions, Has your child taken Albuterol (also known as Ventolin, Pro-air, Proventil)? and please estimate # of days your child had albuterol treatments since the last visit. We used a negative binomial regression analysis with an offset term to adjust for duration of follow-up to get the annualized rate estimate. |
| Number of Participants Who Had Physician Asthma Diagnosis | Follow up duration of 18-48 months | Physician asthma diagnosis were captured at each of the study telephone interviews and clinic visits using the question, Has the doctor told you that your child has asthma?. |
| Annualized Number of Antibiotic Courses | Follow up duration of 18-48 months | The number of antibiotic courses were captured during clinic visits and by telephone interviews every other month using two questions, Has your child taken any antibiotics? and How many separate prescriptions has your child taken of an antibiotic(s)?. We used a negative binomial regression analysis with an offset term to adjust for duration of follow-up to get the annualized rate estimate. |
| Number of Participants Who Experienced Serious Adverse Events | Follow up duration of 18-48 months | Serious Adverse Event were captured during clinic visits and by telephone interviews every other month using designed SAE form. |
| Annualized Number of Oral Corticosteroid Courses | Follow up duration of 18-48 months | The number of oral corticosteroid courses were captured during clinic visits and by telephone interviews every other month using two questions, Has your child taken Oral steroids (Prednisone, Prednisolone, Orapred, Dexamethasone)? and how many separate courses of steroids has your child had since the last visit?. We used a negative binomial regression analysis with an offset term to adjust for duration of follow-up to get the annualized rate estimate. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Azithromycin Participants orally received Azithromycin 10 mg/kg/d for 7 days and 5 mg/kg/d for additional 7 days | 101 |
| Placebo Participants orally received Azithromycin placebo daily for 14 days | 99 |
| Total | 200 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 5 | 7 |
Baseline characteristics
| Characteristic | Azithromycin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 3.9 months | 2.8 months | 3.3 months |
| Birth by cesarean section | 29 Participants | 28 Participants | 57 Participants |
| Birth weight | 3.3 kg STANDARD_DEVIATION 0.5 | 3.4 kg STANDARD_DEVIATION 0.5 | 3.3 kg STANDARD_DEVIATION 0.5 |
| Bronchiolitis severity score | 5.3 Scores on a scale STANDARD_DEVIATION 1.8 | 5.2 Scores on a scale STANDARD_DEVIATION 1.8 | 5.2 Scores on a scale STANDARD_DEVIATION 1.8 |
| Duration of hospital stay | 51 hours | 56 hours | 52 hours |
| Duration of oxygen requirement, if required | 46 hours | 48 hours | 47 hours |
| Food allergy diagnosis | 3 Participants | 5 Participants | 8 Participants |
| Gestational age at birth | 38.9 weeks STANDARD_DEVIATION 1.2 | 38.8 weeks STANDARD_DEVIATION 1.2 | 38.8 weeks STANDARD_DEVIATION 1.2 |
| History of breast feeding | 75 Participants | 80 Participants | 155 Participants |
| History of eczema | 16 Participants | 13 Participants | 29 Participants |
| Lowest oxygen saturation on room air | 90.6 percentage of oxygen saturation STANDARD_DEVIATION 4.4 | 90.7 percentage of oxygen saturation STANDARD_DEVIATION 5.2 | 90.7 percentage of oxygen saturation STANDARD_DEVIATION 4.8 |
| Maternal smoking during pregnancy | 19 Participants | 13 Participants | 32 Participants |
| Need for BiPAP ventilation | 8 Participants | 5 Participants | 13 Participants |
| Other nonstudy antibiotic (nonmacrolide) use | 30 Participants | 28 Participants | 58 Participants |
| Parental history of asthma | 33 Participants | 39 Participants | 72 Participants |
| Parental history of other atopic diseases | 60 Participants | 69 Participants | 129 Participants |
| Pet exposure | 59 Participants | 71 Participants | 130 Participants |
| Race/Ethnicity, Customized Race and ethnicity African American | 19 Participants | 21 Participants | 40 Participants |
| Race/Ethnicity, Customized Race and ethnicity Caucasian | 72 Participants | 72 Participants | 144 Participants |
| Race/Ethnicity, Customized Race and ethnicity More than one race | 10 Participants | 5 Participants | 15 Participants |
| Region of Enrollment United States | 101 Participants | 99 Participants | 200 Participants |
| Sex: Female, Male Female | 47 Participants | 44 Participants | 91 Participants |
| Sex: Female, Male Male | 54 Participants | 55 Participants | 109 Participants |
| Tobacco smoke exposure | 40 Participants | 26 Participants | 66 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 101 | 0 / 99 |
| other Total, other adverse events | 73 / 101 | 72 / 99 |
| serious Total, serious adverse events | 15 / 101 | 16 / 99 |
Outcome results
Primary
Number of Participants Who Experienced the Occurrence of a Third Episode of Post-RSV Wheezing (Recurrent Wheeze)
Episodes of wheezing were captured at each of the study telephone interviews and clinic visits using the question, Has your child's chest sounded wheezy or whistling (with and without a cold)?. A new wheezing episode was defined if at least 7 days without wheezing had been reported since the previous episode.
Time frame: Follow up duration of 18-48 months
Population: A total of 188 participants (96 in the azithromycin group and 92 in the placebo group) had at least one follow-up visit were included in the final primary outcome analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin | Number of Participants Who Experienced the Occurrence of a Third Episode of Post-RSV Wheezing (Recurrent Wheeze) | 45 Participants |
| Placebo | Number of Participants Who Experienced the Occurrence of a Third Episode of Post-RSV Wheezing (Recurrent Wheeze) | 33 Participants |
Comparison: The primary analysis tested the statistical null hypothesis of equal recurrent wheeze rates between the azithromycin and placebo groups.p-value: 0.0895% CI: [0.95, 2.34]Log Rank
p-value: 0.1195% CI: [0.92, 2.29]Regression, Cox
Secondary
Annualized Number of Antibiotic Courses
The number of antibiotic courses were captured during clinic visits and by telephone interviews every other month using two questions, Has your child taken any antibiotics? and How many separate prescriptions has your child taken of an antibiotic(s)?. We used a negative binomial regression analysis with an offset term to adjust for duration of follow-up to get the annualized rate estimate.
Time frame: Follow up duration of 18-48 months
Population: A total of 188 participants (96 in the azithromycin group and 92 in the placebo group) had at least one follow-up visit were included in this analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Azithromycin | Annualized Number of Antibiotic Courses | 1.2 courses per year |
| Placebo | Annualized Number of Antibiotic Courses | 1.3 courses per year |
p-value: 0.5695% CI: [0.7, 1.22]Negative Binomial Regression Analysis
Secondary
Annualized Number of Days With Albuterol Use
The number of days with albuterol use were captured during clinic visits and by telephone interviews every other month using two questions, Has your child taken Albuterol (also known as Ventolin, Pro-air, Proventil)? and please estimate # of days your child had albuterol treatments since the last visit. We used a negative binomial regression analysis with an offset term to adjust for duration of follow-up to get the annualized rate estimate.
Time frame: Follow up duration of 18-48 months
Population: A total of 188 participants (96 in the azithromycin group and 92 in the placebo group) had at least one follow-up visit were included in this analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Azithromycin | Annualized Number of Days With Albuterol Use | 4 days per year |
| Placebo | Annualized Number of Days With Albuterol Use | 3.3 days per year |
p-value: 0.5795% CI: [0.6, 2.48]Negative Binomial Regression Analysis
Secondary
Annualized Number of Days With Respiratory Symptoms (Wheezing, Cough, or Shortness of Breath)
The number of days with respiratory symptoms were captured during clinic visits and by telephone interviews every other month using two questions, Does your child have coughing, wheezing, shortness of breath or chest tightness during the daytime?, If yes, estimate the number of days. We used a negative binomial regression analysis with an offset term to adjust for duration of follow-up to get the annualized rate estimate.
Time frame: Follow up duration of 18-48 months
Population: A total of 188 participants (96 in the azithromycin group and 92 in the placebo group) had at least one follow-up visit were included in this analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Azithromycin | Annualized Number of Days With Respiratory Symptoms (Wheezing, Cough, or Shortness of Breath) | 26.2 days per year |
| Placebo | Annualized Number of Days With Respiratory Symptoms (Wheezing, Cough, or Shortness of Breath) | 22.2 days per year |
p-value: 0.3195% CI: [0.86, 1.62]Negative Binomial Regression Analysis
Secondary
Annualized Number of Oral Corticosteroid Courses
The number of oral corticosteroid courses were captured during clinic visits and by telephone interviews every other month using two questions, Has your child taken Oral steroids (Prednisone, Prednisolone, Orapred, Dexamethasone)? and how many separate courses of steroids has your child had since the last visit?. We used a negative binomial regression analysis with an offset term to adjust for duration of follow-up to get the annualized rate estimate.
Time frame: Follow up duration of 18-48 months
Population: A total of 188 participants (96 in the azithromycin group and 92 in the placebo group) had at least one follow-up visit were included in this analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Azithromycin | Annualized Number of Oral Corticosteroid Courses | 0.23 courses per year |
| Placebo | Annualized Number of Oral Corticosteroid Courses | 0.17 courses per year |
p-value: 0.3895% CI: [0.7, 2.57]Negative Binomial Regression Analysis
Secondary
Number of Participants Who Experienced Serious Adverse Events
Serious Adverse Event were captured during clinic visits and by telephone interviews every other month using designed SAE form.
Time frame: Follow up duration of 18-48 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin | Number of Participants Who Experienced Serious Adverse Events | 15 Participants |
| Placebo | Number of Participants Who Experienced Serious Adverse Events | 16 Participants |
Secondary
Number of Participants Who Had Physician Asthma Diagnosis
Physician asthma diagnosis were captured at each of the study telephone interviews and clinic visits using the question, Has the doctor told you that your child has asthma?.
Time frame: Follow up duration of 18-48 months
Population: A total of 188 participants (96 in the azithromycin group and 92 in the placebo group) had at least one follow-up visit were included in the analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Azithromycin | Number of Participants Who Had Physician Asthma Diagnosis | 15 Participants |
| Placebo | Number of Participants Who Had Physician Asthma Diagnosis | 8 Participants |
p-value: 0.1295% CI: [0.83, 4.61]Log Rank