Asthma, Wheezing
Conditions
Keywords
Asthma, Wheezing, Fluticasone, Montelukast, Preschool-age
Brief summary
The INFANT study will test whether, in preschool children 12-59 months of age with persistent asthma, the following Step 2 asthma therapies will provide similar degrees of asthma control: 1. Daily inhaled corticosteroid (ICS) treatment, 2. Daily leukotriene receptor antagonist (LTRA) treatment, and 3. As-needed ICS plus short-acting beta agonist (as-needed ICS/SABA) rescue treatment.
Detailed description
INFANT is a double-blind, randomized clinical trial in which all participants will receive each of the three therapies for 16 weeks by means of a cross-over study design. INFANT aims to determine whether individual children respond better to one treatment than another and, if so, whether those children can be identified by phenotypic characteristics or selected biomarkers. In this regard the INFANT study is expected to address critical gaps in current asthma management guidelines. Ultimately, the findings from this study are expected to help clarify treatment modalities for this population of young preschool children who are extremely difficult to treat.
Interventions
DRUGdaily fluticasone propionate
Flovent® HFA, 44 mcg per inhalation, 2 inhalations twice daily
DRUGMontelukast
Singulair®, 4 mg granules or chewable tablets by mouth once daily in the evening
DRUGas-needed fluticasone propionate
Flovent® HFA, 44 mcg per inhalation, 2 inhalations, as needed for asthma symptoms
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Milton S. Hershey Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Months to 59 Months
Healthy volunteers
No
Inclusion criteria
* 12-59 months of age. * If the child is not currently taking long-term asthma controller therapy (meaning that the child has taken no inhaled corticosteroid or leukotriene receptor antagonist medication whatsoever over the past 6 months), then one of the following criteria must be met: * Daytime asthma symptoms more than two days per week (average over the past 4 weeks), * At least one nighttime awakening from asthma (over the past 4 weeks), * Two or more asthma exacerbations requiring systemic corticosteroids in the previous 6 months, * Four or more wheezing episodes in the previous 12 months. * If the child is currently taking long-term asthma controller therapy (meaning that the child has taken daily or intermittent/as-needed inhaled corticosteroid or leukotriene receptor antagonist over the past 6 months), then one of the following criteria must be met: * Taking inhaled corticosteroid or leukotriene receptor antagonist for more than 3 months (or more than 90 days) out of the previous 6 months (or 180 days), * Daytime asthma symptoms more than two days per week (average over the past 4 weeks), * More than one nighttime awakening from asthma (over the past 4 weeks), * Two or more asthma exacerbations requiring systemic corticosteroids in the previous 12 months, * Four or more wheezing episodes in the previous 12 months. * Up to date with immunizations, including varicella (unless the subject has already had clinical varicella). * Willingness to provide informed consent by the child's parent or guardian.
Exclusion criteria
* Allergic reaction to the study medications or any component of the study drugs, including (but not limited to) urticaria, rash, angioedema, or hypotension following delivery, * Chronic medical disorders that could interfere with drug metabolism/excretion (for instance chronic hepatic, biliary, or renal disease), * Chronic medical disorders that may increase the risk of drug-related injury, including (but not limited to): * Osteogenesis imperfecta (increased risk of bone demineralization/fracture with corticosteroid therapy), * Crohn's disease, ulcerative colitis, juvenile rheumatoid arthritis, clotting disorders, or Factor deficiency (increased risk of bleeding with corticosteroid therapy), * G6PD deficiency (increased risk of hemolytic anemia with acetaminophen use), * Phenylketonuria (potential for aspartame exposure with study interventions), * Seizure disorder treated with anticonvulsants (risk of acetaminophen toxicity with carbamazepine), or * History of clotting disorders or Factor deficiency (increased risk of bleeding with corticosteroids), * Co-morbid disorders associated with wheezing including (but not limited to) immune deficiency disorders, cystic fibrosis, aspiration, clinically-relevant gastroesophageal reflux, tracheomalacia, congenital airway anomalies (clefts, fistulas, slings, rings), bronchiectasis, bronchopulmonary dysplasia, and/or history of premature birth before 35 weeks gestation, * Significant developmental delay/failure to thrive, defined as 5th percentile for height and/or weight or crossing of two major percentile lines during the last year for age and sex, * History of a near-fatal asthma exacerbation requiring intubation or assisted ventilation, * No primary medical caregiver (e.g., a nurse practitioner, physician assistant, physician, or group medical practice such as a hospital-based clinic) whom the subject can contact for primary medical care, * Three or more hospitalizations in the previous 12 months for wheezing or respiratory illnesses, * Treatment with 5 or more courses of systemic corticosteroids (oral, intramuscular or intravenous) in the past 6 months, * Current use of higher than step 2 NAEPP asthma guideline therapy * If receiving allergy shots, change in the dose within the past 3 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Differential Response to the Three Therapies Based on Fixed Threshold Criteria for the Following Asthma Control Measures: Use of Oral Prednisone for Acute Asthma Exacerbations and Asthma Control Days. | The last 14 weeks of each 16-week treatment period | The primary outcome was differential response to the three therapies on the basis of fixed threshold criteria for the following asthma control measures, which encompassed domains of risk and impairment: the time from the start of the treatment period to an asthma exacerbation treated with systemic corticosteroids, and the annualized number of asthma control days (ACDs) from within that period. ACDs were defined as full calendar days without symptoms, rescue medication use, or unscheduled healthcare visits. Children were defined as differential responders if, first, the time to an asthma exacerbation was at least four weeks longer, or second, if the number of annualized ACDs was at least 31 days more for one treatment than another, in that order. If neither threshold was met, the participant was considered a non differential responder. Differential response was determined in children completing at least two treatment periods and at least 50% of the daily diary entries for each period. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Crossover Sequence 1 daily fluticasone propionate, followed by daily montelukast, followed by as needed fluticasone propionate | 50 |
| Crossover Sequence 2 daily fluticasone propionate, followed by as needed fluticasone propionate, followed by daily montelukast | 49 |
| Crossover Sequence 3 daily montelukast, followed by as needed fluticasone propionate, followed by daily fluticasone propionate | 51 |
| Crossover Sequence 4 daily montelukast, followed by daily fluticasone propionate, followed by as needed fluticasone propionate | 51 |
| Crossover Sequence 5 as needed fluticasone propionate, followed by daily fluticasone propionate, followed by daily montelukast | 52 |
| Crossover Sequence 6 as needed fluticasone propionate, followed by daily montelukast, followed by daily fluticasone propionate | 47 |
| Total | 300 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 1 | 1 | 2 | 0 |
| Overall Study | Lack of Efficacy | 2 | 1 | 4 | 4 | 1 | 2 |
| Overall Study | Lost to Follow-up | 7 | 4 | 5 | 4 | 3 | 5 |
| Overall Study | Physician Decision | 1 | 2 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 3 | 4 | 4 | 5 | 4 |
Baseline characteristics
| Characteristic | Crossover Sequence 1 | Crossover Sequence 2 | Crossover Sequence 3 | Crossover Sequence 4 | Crossover Sequence 5 | Crossover Sequence 6 | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 50 Participants | 49 Participants | 51 Participants | 51 Participants | 52 Participants | 47 Participants | 300 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 38.3 months STANDARD_DEVIATION 13.6 | 40.7 months STANDARD_DEVIATION 12.4 | 38.7 months STANDARD_DEVIATION 11.6 | 38.6 months STANDARD_DEVIATION 15.1 | 41.7 months STANDARD_DEVIATION 12.7 | 41.2 months STANDARD_DEVIATION 14 | 39.9 months STANDARD_DEVIATION 13.2 |
| Allergen Test Negative test | 32 participants | 29 participants | 31 participants | 30 participants | 27 participants | 30 participants | 179 participants |
| Allergen Test Positive test | 18 participants | 20 participants | 20 participants | 21 participants | 25 participants | 17 participants | 121 participants |
| Blood eosinophils | 183 number of cells per micro-liter | 234 number of cells per micro-liter | 258 number of cells per micro-liter | 255 number of cells per micro-liter | 308 number of cells per micro-liter | 310 number of cells per micro-liter | 258 number of cells per micro-liter |
| Eczema Not Present | 29 participants | 21 participants | 24 participants | 23 participants | 26 participants | 17 participants | 140 participants |
| Eczema Present | 21 participants | 28 participants | 27 participants | 28 participants | 26 participants | 30 participants | 160 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants | 12 Participants | 10 Participants | 11 Participants | 12 Participants | 10 Participants | 72 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants | 37 Participants | 41 Participants | 40 Participants | 40 Participants | 37 Participants | 228 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Hospitalized in past 12 months Hospitalized | 9 participants | 14 participants | 11 participants | 6 participants | 13 participants | 12 participants | 65 participants |
| Hospitalized in past 12 months Not hospitalized | 41 participants | 35 participants | 40 participants | 45 participants | 39 participants | 35 participants | 235 participants |
| Parental Asthma Not Present | 20 participants | 20 participants | 22 participants | 19 participants | 17 participants | 24 participants | 122 participants |
| Parental Asthma Present | 30 participants | 29 participants | 29 participants | 32 participants | 35 participants | 23 participants | 178 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 15 Participants | 20 Participants | 13 Participants | 20 Participants | 18 Participants | 97 Participants |
| Race (NIH/OMB) More than one race | 10 Participants | 6 Participants | 7 Participants | 5 Participants | 10 Participants | 7 Participants | 45 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 25 Participants | 27 Participants | 24 Participants | 30 Participants | 21 Participants | 21 Participants | 148 Participants |
| Region of Enrollment United States | 50 participants | 49 participants | 51 participants | 51 participants | 52 participants | 47 participants | 300 participants |
| Serum IgE | 67 international units per liter | 106.5 international units per liter | 64 international units per liter | 64 international units per liter | 87 international units per liter | 84 international units per liter | 70 international units per liter |
| Sex: Female, Male Female | 20 Participants | 20 Participants | 19 Participants | 21 Participants | 18 Participants | 23 Participants | 121 Participants |
| Sex: Female, Male Male | 30 Participants | 29 Participants | 32 Participants | 30 Participants | 34 Participants | 24 Participants | 179 Participants |
| Systemic corticosteroids in past 12 monts Not used | 13 participants | 14 participants | 14 participants | 11 participants | 13 participants | 11 participants | 76 participants |
| Systemic corticosteroids in past 12 monts Used | 37 participants | 35 participants | 37 participants | 40 participants | 39 participants | 36 participants | 224 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 212 / 300 | 206 / 300 | 212 / 300 |
| serious Total, serious adverse events | 2 / 300 | 8 / 300 | 8 / 300 |
Outcome results
Primary
Differential Response to the Three Therapies Based on Fixed Threshold Criteria for the Following Asthma Control Measures: Use of Oral Prednisone for Acute Asthma Exacerbations and Asthma Control Days.
The primary outcome was differential response to the three therapies on the basis of fixed threshold criteria for the following asthma control measures, which encompassed domains of risk and impairment: the time from the start of the treatment period to an asthma exacerbation treated with systemic corticosteroids, and the annualized number of asthma control days (ACDs) from within that period. ACDs were defined as full calendar days without symptoms, rescue medication use, or unscheduled healthcare visits. Children were defined as differential responders if, first, the time to an asthma exacerbation was at least four weeks longer, or second, if the number of annualized ACDs was at least 31 days more for one treatment than another, in that order. If neither threshold was met, the participant was considered a non differential responder. Differential response was determined in children completing at least two treatment periods and at least 50% of the daily diary entries for each period.
Time frame: The last 14 weeks of each 16-week treatment period
Population: Differential response was determined in children completing at least two treatment periods and at least 50% of the daily diary entries for each period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Evaluable Participants | Differential Response to the Three Therapies Based on Fixed Threshold Criteria for the Following Asthma Control Measures: Use of Oral Prednisone for Acute Asthma Exacerbations and Asthma Control Days. | Non-differential responders | .26 probability |
| All Evaluable Participants | Differential Response to the Three Therapies Based on Fixed Threshold Criteria for the Following Asthma Control Measures: Use of Oral Prednisone for Acute Asthma Exacerbations and Asthma Control Days. | Responded best to daily ICS | .40 probability |
| All Evaluable Participants | Differential Response to the Three Therapies Based on Fixed Threshold Criteria for the Following Asthma Control Measures: Use of Oral Prednisone for Acute Asthma Exacerbations and Asthma Control Days. | Responded best to daily LTRA | .18 probability |
| All Evaluable Participants | Differential Response to the Three Therapies Based on Fixed Threshold Criteria for the Following Asthma Control Measures: Use of Oral Prednisone for Acute Asthma Exacerbations and Asthma Control Days. | Responded best to as-needed ICS | .16 probability |
Comparison: The primary analysis tested the null hypothesis of all three treatments having equal probability to yield the best response as defined by the criteria defining the primary outcome. A sample size of 300 participants was selected to test the primary null hypothesis of all three treatments having equal probability (one-third) to yield the best response with statistical power of at least 0.90 if any one of the three treatments actually has probability of at least one-half to yield the best response.p-value: <0.0001rank-order logistic regression