Individualized Therapy For Asthma in Toddlers (INFANT)

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.

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.

• Asthma
• Wheezing

• Drug: daily fluticasone propionate
  Flovent® HFA, 44 mcg per inhalation, 2 inhalations twice daily
• Drug: Montelukast
  Singulair®, 4 mg granules or chewable tablets by mouth once daily in the evening
• Drug: as-needed fluticasone propionate
  Flovent® HFA, 44 mcg per inhalation, 2 inhalations, as needed for asthma symptoms

• Experimental: Crossover sequence 1
  daily fluticasone propionate, followed by daily montelukast, followed by as needed fluticasone propionate
  Interventions:

  • Drug: daily fluticasone propionate
  • Drug: Montelukast
  • Drug: as-needed fluticasone propionate
• Experimental: Crossover sequence 2
  daily fluticasone propionate, followed by as needed fluticasone propionate, followed by daily montelukast
  Interventions:

  • Drug: daily fluticasone propionate
  • Drug: Montelukast
  • Drug: as-needed fluticasone propionate
• Experimental: Crossover sequence 3
  daily montelukast, followed by as needed fluticasone propionate, followed by daily fluticasone propionate
  Interventions:

  • Drug: daily fluticasone propionate
  • Drug: Montelukast
  • Drug: as-needed fluticasone propionate
• Experimental: Crossover sequence 4
  daily montelukast, followed by daily fluticasone propionate, followed by as needed fluticasone propionate
  Interventions:

  • Drug: daily fluticasone propionate
  • Drug: Montelukast
  • Drug: as-needed fluticasone propionate
• Experimental: Crossover sequence 5
  as needed fluticasone propionate, followed by daily fluticasone propionate, followed by daily montelukast
  Interventions:

  • Drug: daily fluticasone propionate
  • Drug: Montelukast
  • Drug: as-needed fluticasone propionate
• Experimental: Crossover sequence 6
  as needed fluticasone propionate, followed by daily montelukast, followed by daily fluticasone propionate
  Interventions:

  • Drug: daily fluticasone propionate
  • Drug: Montelukast
  • Drug: as-needed fluticasone propionate

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.