Nasal Budesonide in Children With Rhinitis and/or Mild Obstructive Sleep Apnea Syndrome
Nasal Budesonide in Children With Rhinitis and/or Mild Obstructive Sleep Apnea Syndrome
-Intranasal budesonide therapy may lead to improved symptoms and sleep study findings in
 children with mild obstructive sleep apnea with and without allergic rhinitis that would not
 be treated with T&A. The aim of the study is to conduct a randomized double blind cross-over
 trial comparing the effect of once a day intranasal budesonide therapy vs. placebo in
 children with mild sleep apnea that would not be candidates for T&A.
Untreated OSAS can result in serious morbidity, primarily affecting neurobehavioral and
 cardiovascular systems.

 The severity of OSAS is only partially related to the adenoid and tonsillar size. While
 adenotonsillectomy (T&A) is the most common treatment for children with OSAS, this approach
 is reserved for children whose apnea/hypopnea index in the overnight sleep study exceeds a
 critical value. However, there is no consensus on the appropriate management of children with
 AHI >1 but <7 events/hour of sleep. These children constitute between 4-6% of all children
 and there are no alternative long-term interventions, and therefore a medical approach that
 obviates surgery, yet leads to substantial amelioration in the sleep-disordered breathing is
 critically needed.

 Anti-inflammatory agents like intra-nasal corticosteroids are considered an effective
 treatment for children with allergic rhinitis. However, only one study has been conducted so
 far, and has examined the effect of intranasal corticosteroids, in pediatric patients with
 florid OSAS. Thus, no studies are available on topical steroids in patients with OSAS
 severity that would not justify T&A.

 Our leading hypothesis is:

 - Intranasal budesonide therapy may lead to improved symptoms and polysomnographic findings
 in children with OSAS with and without allergic rhinitis that would not be treated with T&A.

 Subjects And Methods Study population Specific Aim. Up to 100 children will be recruited from
 all pediatric patients referred for evaluation of snoring and who underwent clinical
 evaluation, lateral neck x-ray, and an overnight sleep study at the Kosair Children's
 Hospital Sleep Medicine and Apnea Center.

 Study Design Specific Aim: After informed consent is obtained from the parents, children
 fulfilling the entry criteria will be randomized using a table of random numbers that will be
 provided by Astra-Zeneca. Patients will be allocated into parallel treatment groups with
 simple randomization in blocks of 4 in a double blind fashion, according to the randomization
 procedure delineated by Astra-Zeneca All patients will complete a questionnaire regarding
 symptoms of snoring and allergic rhinitis symptoms prior to starting the study. One of the
 groups will start a-6 week course of either nasal topical budesonide (32 mcg/puff/nostril to
 both nostrils (total of 64 mcg), once a day or placebo. Parents will be instructed to give
 the drug at bedtime. Parents will be contacted weekly by the investigators to determine
 whether the study drug is being given as prescribed. When unable to contact parents by phone,
 they will be sent a follow up letter accompanied with the weekly questionnaire and a
 postage-paid return envelope. After 6 weeks, patients will have an overnight sleep study,
 lateral neck x-ray, and they will fill in a questionnaire regarding snoring and rhinitis
 symptoms.. At the end of the 6 weeks, patients will start a 6-week course with the compound
 that they were not receiving during the 1st phase of the study. All the outcome endpoints
 will be assessed again upon completion of the 2nd 6-week course.

 The overall rationale for this schedule is as follows:

 We are aiming to assess whether intranasal budesonide is effective in ameliorating
 sleep-disordered breathing in these children. Therefore, we aim to maximize the number of
 children receiving intranasal budesonide. This is achieved in the above experimental scheme
 since all children will receive 6 weeks of the therapy, either at the onset of their 12-week
 participation or after 6 weeks (for those who will be randomized to placebo treatment in the
 initial 6 weeks). The rationale for a 6-week duration period is that we anticipate that the
 reduction in adenoid volume will be a slow process that requires between 3-6 weeks to reach
 its peak effect. We also wish to determine whether cessation of intranasal budesonide is
 associated with exacerbation of the SDB. To this effect, the group of children who were
 initially treated with budesonide for 6 weeks will provide the data towards answering this
 important question. We anticipate that rebound increase in severity will occur but may take
 several weeks to manifest since the incremental growth of adenoid tissue will also take time.

 Both nasal-budesonide and placebo inhalers will be provided in identical containers by the
 drug manufacturer. The appearance and smell of the budesonide and placebo will be
 indistinguishable. The investigators will not be aware of the compound being used. The codes
 for each patient will be kept by Astra-Zeneca. If any adverse event develops, the patients
 will be withdrawn from the study and followed clinically to assess overall clinical course.

 Experimental Protocols

 Symptoms questionnaire All patients will fill a snoring and symptom questionnaire.

 Lateral Neck X-Rays This will be performed using standard techniques in the Radiology
 Department at KCH.

 Overnight Polysomnography All children participating in the study will be
 polysomnographically studied before inclusion as part of their routine clinical evaluation.
 In addition, they will undergo 2 additional sleep studies, each at the end of the 6-week
 intervention period of the study.

 Statistics A sample size of 50 patients per arm in this parallel design study was estimated
 based on an alpha error of 0.05, beta error of 0.2, a baseline mean apnea hypopnea index
 (AHI) of 3, with an SD of 1.5, and a potential decrease in AHI by 20%. In addition, such
 number of subjects would allow for detection of a 30% improvement in rhinitis scores. Even if
 attrition occurs, 40 subjects per arm will be sufficient assuming a 30% improvement in AHI
 according to sleep study. This design and number will also permit accurate determination of
 rebound exacerbation following transition from budesonide to placebo in half the subjects.
 (see above). Results will be expressed as the mean +/- SEM. To assess treatment
 effectiveness, paired t-tests will be used to compare normally distributed variables.

 Potential Risks Nasal budesonide (Rhinocort Aqua, AstraZeneca) is generally well tolerated..
 The most commonly reported adverse events( more then 2%) for Rhinocort Aqua and vehicle
 placebo (a formulation with no active drug) respectively were: epistaxis (nosebleed) - 8
 percent vs 5 percent; pharyngitis (sore throat) - 4 percent vs 3 percent; bronchospasm 2
 percent vs 1 percent; nasal irritation - 2 percent vs <1 percent; and coughing - 2 percent vs
 <1 percent.

 Rare adverse events reported include: nasal septum perforation, pharynx disorders (throat
 irritation or pain, swollen throat, burning throat, itching throat, angioedema, anosmia and
 palpitations. Even though, studies have shown detectable adrenal suppression with intranasal
 steroids administration,30 intranasal budesonide 200 µg once daily has been found to have no
 effects on 24 hour, or fractionated cortisol profiles in serum or urine.31 And although
 transient growth suppression have been reported with medium to high dose inhaled steroids, no
 similar side effects were reported during clinical studies with intranasal budesonide.
 Furthermore, the addition of intranasal budesonide therapy to medium dose of inhaled
 budesonide in children with asthma for approximately 24 months had no significant effect on
 final adult height.32

 Potential Benefits It is possible that the participants will have improvements in the
 severity of their OSAS and their snoring severity during nasal budesonide therapy.

 The information obtained in our study, will help to define the role of nasal budesonide
 intervening in the pathophysiology of OSAS, and the potential role of nasal budesonide as a
 nonsurgical therapy for children with otherwise mild OSAS who would not be considered as
 candidates for T&A.

 Significance of Research For children with OSAS that is too mild to justify T&A surgery,
 Intranasal therapy with budesonide may become a safe and effective new therapy aiming to
 minimize the morbidity associated with OSAS in children.
Inclusion Criteria:

 -  Children >6 years of age and < 12 years of age, who snore and have an apnea hypopnea
 index (AHI) < or equal 7 or Respiratory arousal index > or equal 2

 Exclusion Criteria:

 -  Hypersensitivity to budesonide

 -  Recent nasal trauma

 -  Nasal surgery or nasal septum perforation

 -  Current therapy with drugs interacting with budesonide (erythromycin clarythromycin,
 ketoconazole and cimetidine)

 -  Immunodeficiency or immunosuppressant therapy

 -  Craniofacial, neuromuscular, syndromic or defined genetic abnormalities

 -  Acute upper respiratory tract infection

 -  Systemic corticosteroid therapy or antibiotic therapy in the 2 weeks previous to the
 study, and

 -  Children who already had adenotonsillectomy in the past 12 months.