Asthma, Wheezing
Conditions
Keywords
Asthma, Wheezing, Respiratory Tract Illness, Azythromycin, Prednisolone, Preschool-age
Brief summary
This protocol is comprised of two separate, but linked, clinical trials for treating preschool-aged children with recurrent severe episodes of wheezing. The first study (APRIL) will try to prevent wheezing illness from developing using azithromycin. If a wheezing illness does occur, the second trial (OCELOT) will try to decrease the severity of symptoms using oral corticosteroids.
Detailed description
Preschool aged children often have severe bouts of coughing and/or wheezing that lead to visits to the doctor's office, urgent care, emergency room and often hospitalization. APRIL-OCELOT is a randomized, double-blind, placebo controlled study in 600 preschool children with a history of significant wheezing episodes in the year prior to enrollment. All children enter the APRIL portion of the study, which will compare azithromycin to placebo, given for 5 days during the early signs of an upper respiratory tract illness, for preventing the development of lower respiratory tract symptoms. APRIL is a 78 week study, but participation will end earlier if the child requires a fourth course of APRIL treatment or develops significant lower respiratory tract symptoms. Only those children who develop significant lower respiratory tract symptoms during APRIL will enter the OCELOT portion of the study, which will compare oral corticosteroid to placebo for treating lower respiratory tract symptoms as measured by the Pediatric Respiratory Assessment Measure (PRAM). OCELOT participation will be complete after 14 days. Children may not reenter APRIL after completing OCELOT.
Interventions
DRUGAzithromycin
Suspension, 12 mg/kg once daily for 5 days, maximum dose 500mg/day
DRUGPrednisolone
Syrup, 1 mg/kg/dose twice daily for 5 days, maximum dose 60mg/day
OTHERPlacebo Azithromycin
Suspension, 12 mg/kg once daily for 5 days, maximum dose 500mg/day
Syrup, 1 mg/kg/dose twice daily for 5 days, maximum dose 60mg/day
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 71 Months
Healthy volunteers
No
Inclusion criteria
* 12-71 months of age. * Recurrent significant wheezing in the past year (any of the following): * \>3 episodes, ≥1 of which was clinically significant\*; OR * \>2 clinically significant\* episodes; OR * \>4 months of daily controller therapy AND \>1 clinically significant\* episode. * \* Clinically significant episode: requiring any of the following: (1) systemic corticosteroids (oral or injectable), (2) unscheduled physician office visit, (3) ED visit, (4) urgent care visit, or (5) hospitalization. * Up to date with immunizations, including varicella (unless the subject has already had clinical varicella). If the subject needs varicella vaccine, this will be arranged with the primary care physician and must be received prior to randomization. * Willingness to provide informed consent by the child's parent or guardian.
Exclusion criteria
Participants who meet any of the following criteria are NOT eligible for enrollment, but may be re-enrolled if these
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression to Clinically Significant Lower Respiratory Tract Symptoms | 14 days after initiation of APRIL therapy | Progression to clinically significant lower respiratory tract symptoms defined by: (1) having symptoms that were more than mild after 3 albuterol administrations over 1 hour, or (2) requiring albuterol administrations more often than once every 4 hours, or (3) requiring more than 6 albuterol treatments over a 24-hour period, or (4) having moderate to severe cough or wheeze for 5 or more days since study medication was initiated. |
| OCELOT: Pediatric Respiratory Assessment Measure | 36-72 hours after initiation of OCELOT therapy | The Pediatric Respiratory Assessment Measure (PRAM) is a composite outcome with scores ranging from 0-12 with higher numbers representing worse symptoms. The score is calculated as the sum total of the follow five elements: (1) scalene retractions, (2) suprasternal retractions, (3) wheezing, (4) air entry, (5) oxygen saturation. A complete description can be found in: Ducharme FM, Chalut D, Plotnick L, et al. The Pediatric Respiratory Assessment Measure: a valid clinical score for assessing acute asthma severity from toddlers to teenagers. J Pediatr 2008;152:476-80. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Asthma Related Symptoms Among RTI Progressing to Severe LRTI | 14 days after initiation of therapy | Asthma related symptoms as measured by the parent-completed Pre-school Asthma Symptom Diary (PAD). The PAD was completed daily starting on the first day of an illness and continued until the participant was symptom-free for 2 days. It contains questions of frequency of respiratory symptoms, each scored on a scale of 1 through 7, with higher scores representing increasingly frequent symptoms, with daily scores ranging from 0 (asymptomatic) to a maximum of 102. The total PAD score is the sum of the daily individual symptom scores over the duration of the illness, with higher scores representing more frequent symptoms. |
| Absence From School, Daycare, and/or Parental Work | 14 days after initiation of therapy | — |
| Urgent Care Visits, ED Visits and Hospitalizations | 14 days after initiation of therapy | Number of participants who had urgent care visits, ED visits, and/or hospitalizations for respiratory symptoms. |
| Drug Related Side Effects | 14 days after initiation of therapy | Parent-reported gastrointestinal symptoms during treated RTI. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Azythromycin Azithromycin: Suspension, 12 mg/kg once daily for 5 days, maximum dose 500mg/day | 307 |
| Placebo Placebo Azithromycin: Suspension, 12 mg/kg once daily for 5 days, maximum dose 500mg/day | 300 |
| Total | 607 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 31 | 20 | 31 | 23 |
Baseline characteristics
| Characteristic | Placebo | Azythromycin | Total |
|---|---|---|---|
| Age, Continuous | 41.1 months STANDARD_DEVIATION 16.4 | 41.9 months STANDARD_DEVIATION 16.5 | 41.5 months STANDARD_DEVIATION 16.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 92 Participants | 91 Participants | 183 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 208 Participants | 216 Participants | 424 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Gender Female | 118 Participants | 124 Participants | 242 Participants |
| Gender Male | 182 Participants | 183 Participants | 365 Participants |
| Hospitalizations for respiratory symptoms in prior year | 1 Hospitalizations | 1 Hospitalizations | 1 Hospitalizations |
| Race (NIH/OMB) American Indian or Alaska Native | 5 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 7 Participants | 10 Participants |
| Race (NIH/OMB) Black or African American | 77 Participants | 80 Participants | 157 Participants |
| Race (NIH/OMB) More than one race | 30 Participants | 40 Participants | 70 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 185 Participants | 177 Participants | 362 Participants |
| Region of Enrollment United States | 300 participants | 307 participants | 607 participants |
| Urgent care or ED visits in prior year | 2.5 visits STANDARD_DEVIATION 1.6 | 2.5 visits STANDARD_DEVIATION 1.7 | 2.5 visits STANDARD_DEVIATION 1.6 |
| Wheezing episodes in prior year | 4.4 episodes STANDARD_DEVIATION 2.9 | 4.5 episodes STANDARD_DEVIATION 3.4 | 4.5 episodes STANDARD_DEVIATION 3.2 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 179 / 307 | 180 / 300 |
| serious Total, serious adverse events | 18 / 307 | 15 / 300 |
Outcome results
Primary
OCELOT: Pediatric Respiratory Assessment Measure
The Pediatric Respiratory Assessment Measure (PRAM) is a composite outcome with scores ranging from 0-12 with higher numbers representing worse symptoms. The score is calculated as the sum total of the follow five elements: (1) scalene retractions, (2) suprasternal retractions, (3) wheezing, (4) air entry, (5) oxygen saturation. A complete description can be found in: Ducharme FM, Chalut D, Plotnick L, et al. The Pediatric Respiratory Assessment Measure: a valid clinical score for assessing acute asthma severity from toddlers to teenagers. J Pediatr 2008;152:476-80.
Time frame: 36-72 hours after initiation of OCELOT therapy
Population: Participants who developed severe lower respiratory tract infections and initiate blinded OCELOT therapy.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Azythromycin | OCELOT: Pediatric Respiratory Assessment Measure | 0.82 PRAM score | Standard Deviation 1.49 |
| Placebo | OCELOT: Pediatric Respiratory Assessment Measure | 1.00 PRAM score | Standard Deviation 1.41 |
Primary
Progression to Clinically Significant Lower Respiratory Tract Symptoms
Progression to clinically significant lower respiratory tract symptoms defined by: (1) having symptoms that were more than mild after 3 albuterol administrations over 1 hour, or (2) requiring albuterol administrations more often than once every 4 hours, or (3) requiring more than 6 albuterol treatments over a 24-hour period, or (4) having moderate to severe cough or wheeze for 5 or more days since study medication was initiated.
Time frame: 14 days after initiation of APRIL therapy
Population: All participants who initiated APRIL therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azythromycin | Progression to Clinically Significant Lower Respiratory Tract Symptoms | 35 participants |
| Placebo | Progression to Clinically Significant Lower Respiratory Tract Symptoms | 57 participants |
p-value: 0.0495% CI: [0.41, 0.98]Discrete time survival analysis
Secondary
Absence From School, Daycare, and/or Parental Work
Time frame: 14 days after initiation of therapy
Population: Data were of insufficient quality to be analyzed.
Secondary
Asthma Related Symptoms Among RTI Progressing to Severe LRTI
Asthma related symptoms as measured by the parent-completed Pre-school Asthma Symptom Diary (PAD). The PAD was completed daily starting on the first day of an illness and continued until the participant was symptom-free for 2 days. It contains questions of frequency of respiratory symptoms, each scored on a scale of 1 through 7, with higher scores representing increasingly frequent symptoms, with daily scores ranging from 0 (asymptomatic) to a maximum of 102. The total PAD score is the sum of the daily individual symptom scores over the duration of the illness, with higher scores representing more frequent symptoms.
Time frame: 14 days after initiation of therapy
Population: Respiratory Tract Infections (RTI) progressing to Severe Lower RTI
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Azythromycin | Asthma Related Symptoms Among RTI Progressing to Severe LRTI | 140 PAD score | Standard Deviation 74 |
| Placebo | Asthma Related Symptoms Among RTI Progressing to Severe LRTI | 195 PAD score | Standard Deviation 137 |
Secondary
Drug Related Side Effects
Parent-reported gastrointestinal symptoms during treated RTI.
Time frame: 14 days after initiation of therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azythromycin | Drug Related Side Effects | 3 events |
| Placebo | Drug Related Side Effects | 1 events |
Secondary
Urgent Care Visits, ED Visits and Hospitalizations
Number of participants who had urgent care visits, ED visits, and/or hospitalizations for respiratory symptoms.
Time frame: 14 days after initiation of therapy
Population: All participants who initiated APRIL therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azythromycin | Urgent Care Visits, ED Visits and Hospitalizations | 20 participants |
| Placebo | Urgent Care Visits, ED Visits and Hospitalizations | 38 participants |