Obstructive Sleep Apnea Syndrome
Conditions
Keywords
Obstructive sleep apnea syndrome, OSA, sleep apnea, nasal steroids, corticosteroids
Brief summary
This double-blind, randomized controlled trial will evaluate the use of nasal corticosteroids for the treatment of the childhood obstructive sleep apnea syndrome (OSAS). Efficacy, duration of action and side-effects will be determined.
Detailed description
Several studies have suggested that Nasal corticosteroids (NCS) or leukotriene antagonists may be effective in the treatment of childhood OSAS. However, these studies have been limited by factors such as small size, lack of randomization and blinding, short-term follow-up, involvement of children with only very mild OSAS, and/or lack of stratifying for the presence of atopy. Therefore, investigators will plan a randomized controlled trial evaluating the efficacy and safety of NCS vs placebo in children with mild to moderate OSAS. The overall hypothesis is that NCS will be safe and efficacious in the treatment of mild to moderate childhood OSAS, particularly in children with asthma/atopy, but will require ongoing maintenance therapy.
Interventions
DRUGNasal Fluticasone
One spray per nostril, per day.
DRUGPlacebo
One spray per nostril, per day.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Children's Hospital of Philadelphia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
5 Years to 12 Years
Healthy volunteers
No
Inclusion criteria
1. 5-10 years of age. 2. Mild to moderate OSAS, defined as an obstructive apnea index of 1-20/hr of total sleep time or obstructive apnea hypopnea index of 2-30/hr of total sleep time. 3. Parent-related symptoms of habitual snoring (\>3 nights per week) 4. No history of adenotonsillectomy. 5. Parental/guardian permission (informed consent) and if appropriate, child assent
Exclusion criteria
1. Severe OSAS or significant hypoxemia or hypercapnia on polysomnography, such that definitive treatment should not be delayed (AHI \> 30/hr, more than 2% total sleep time with arterial oxygen saturation (SpO2) \<90%, end-tidal carbon dioxide partial pressure (PCO2) \> 60 mm Hg for \> 5 minutes, pathologic arrhythmias). 2. History of recurrent throat infections (as defined by the American Academy of Otolaryngology-Head and Neck Surgery Clinical Practice Guidelines For Tonsillectomy (7)) in the past few years as follows: \> 7 episodes in the past year or \> 5 episodes/year over the past 2 years or \> 3 episodes/year over the past 3 years. 3. Abnormalities on baseline safety screening tests, i.e., Dual Energy X-ray Absorptiometry (DXA) scan showing spine or whole body bone mineral density \< -2.0 standard deviations using race specific curves with adjustment for height Z-score; morning cortisol \< 3 µg/dl or morning adrenocorticotropic hormone (ACTH) \< 10 pg/ml; or ophthalmologic exam demonstrating cataracts (except those with \< 2 mm anterior polar cataracts), aphakia or other ocular abnormalities such as glaucoma, retinal coloboma, intraocular inflammation or microphthalmia. 4. Failure to thrive (weight/height \< 5th percentile for age and gender), as this may be secondary to OSAS. 5. Severe obesity (BMI z-score \> 3) as OSAS is likely to persist in these subjects. 6. Previous adenoidectomy unless adenoidal tissue has been documented to have regrown. 7. Previous tonsillectomy. 8. Continuous positive airway pressure (CPAP) therapy. 9. Any NCS use in the past 3 months or NCS use for \> 2 weeks in the past year. 10. Current immunotherapy or daily antihistamine use. 11. Recent (past month) nasal septum ulcers, surgery or trauma. 12. Other major illness other than asthma, such as craniofacial anomalies, endocrine or neuromuscular disease, or past history of cancer. This includes children with conditions that may be worsened by OSAS, such as hypertension or diabetes. 13. Current use of ketoconazole or other potent CYP3A4 inhibitors. 14. Families planning to move out of the area within the year. 15. Subjects who do not speak either English or Spanish well enough to complete the validated neurobehavioral instruments. 16. Parents/guardians or subjects who, in the opinion of the Investigator, may be non-compliant with study schedules or procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Obstructive Apnea Hypopnea Index | 3 months | Efficacy measure to assess acute response to nasal steroids. Obstructive apnea hypopnea index (events per hour). Per inclusion/exclusion criteria the expected range for this study at baseline is between 2 and 30 events per hour. Please note that lower and upper ranges can be broader at the 3- and 12-month points. The obstructive apnea hypopnea index (OAHI) is the sum of obstructive apneas and hypopneas, and mixed apneas divided by the total hours of sleep. Hence, the unit used is events per hour. It ranges from 0 events per hour(meaning no obstructive apneas at all) until 400 events per hour approximately. Higher values indicate more severe obstructive sleep apnea or worse outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Nasal Obstruction Symptom Evaluation (NOSE) | 12 months | Nasal Obstruction Symptom Evaluation (NOSE) scale, a validated scale of nasal obstructive symptoms. The scales ranges from 0-100 with higher values indicating worse nasal obstruction |
| The Epworth Sleepiness Scale | 12 months | Epworth Sleepiness scale is a measure of sleepiness that ranges from 0-24, with higher values indicating sleepiness |
| Pediatric Quality of Life Inventory (PedsQL) | 12 month | Pediatric Quality of Life Inventory (PedsQL), a well-validated, generic measure of global quality of life, in which scores range from 0 to 100, with higher scores indicating better quality of life |
| Behavior Rating Inventory of Executive Function (BRIEF) | 12 months | Behavior Rating Inventory of Executive Function \[BRIEF\] Global Executive Composite T score, comprising summary measures of behavioral regulation and metacognition \[with mean scores of 50 and standard deviation of 10, with higher scores indicating worse functioning\] |
| OAHI | 12 months | Efficacy measure to assess duration of response to nasal steroids. Obstructive apnea hypopnea index (events per hour). Per inclusion/exclusion criteria the expected range for this study at baseline is between 2 and 30 events per hour. Please note that lower and upper ranges can be broader at the 3- and 12-month points. |
| Purdue Peg Board | 12 months | The Purdue Peg Board is a widely used test of fine motor coordination, yields z-scores with a mean of 0 and a standard deviation of 1, with higher scores indicating better performance. |
| Conners Continuous Performance Test (CPT) | 12 months | The CPT is a performance measure of sustained attention that yields T scores with a mean of 50 and a standard deviation of 10 (higher scores indicate worse functioning) |
| Child Behavior Checklist | 12-Months | The Child Behavior Checklist (CBCL), is a widely used and validated caregiver-completed survey of behavior competencies that yields standardized, age-adjusted scores on internalizing, externalizing and attentional behavior difficulties81, 82. All scores are T scores with a mean of 50 and standard deviation of 10 (higher scores indicate worse functioning). |
| Conners Abbreviated Symptom Questionnaire | 12 months | A parent-rated measure of symptoms of attention problems, yielding T scores with a mean of 50 and a standard deviation of 10 (higher scores indicate worse functioning). |
Countries
United States
Participant flow
Pre-assignment details
Screening: polysomnography, ophthalmologic exam, DXA scan. 75 children did not meet PSG inclusion criteria, 1 child had a coloboma, and 1 child had abnormal DXA scan.
Participants by arm
| Arm | Count |
|---|---|
| Nasal Steroids Participants randomly assigned to this study arm will receive a 3-month course of nasal steroids (nasal fluticasone).
Nasal Fluticasone: One spray per nostril, per day. | 91 |
| Placebo Participants randomly assigned to this study arm will receive a 3-month course of placebo nasal spray (saline).
Placebo: One spray per nostril, per day. | 43 |
| Total | 134 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 5 | 7 |
Baseline characteristics
| Characteristic | Placebo | Nasal Steroids | Total |
|---|---|---|---|
| Age, Continuous | 8.10 years STANDARD_DEVIATION 2.03 | 8.24 years STANDARD_DEVIATION 2.17 | 8.17 years STANDARD_DEVIATION 2.1 |
| Behavior Rating Inventory of Executive Function (BRIEF) | 47.11 T-Score | 50.86 T-Score | 48.985 T-Score |
| Conners Abbreviated Symptom Questionnaire | 5.97 T-Score | 8.19 T-Score | 7.08 T-Score |
| Conners Continuous Performance Test (CPT) | 56.1 T-Score | 54.8 T-Score | 55.45 T-Score |
| Nasal Obstrction Symptoms Evaluation (NOSE) | 4.47 units on a scale | 5.59 units on a scale | 5.03 units on a scale |
| OAHI | 6.51 events per hour | 7.85 events per hour | 7.52 events per hour |
| Pediatric Quality of Life (PedsQL) | 78.44 units on a scale | 73.91 units on a scale | 76.175 units on a scale |
| Purdue Peg Board | -1.39 z-Score | -1.06 z-Score | -1.225 z-Score |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 25 Participants | 65 Participants | 90 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 13 Participants | 16 Participants | 29 Participants |
| Race (NIH/OMB) White | 5 Participants | 10 Participants | 15 Participants |
| Region of Enrollment United States | 43 participants | 91 participants | 134 participants |
| Sex: Female, Male Female | 20 Participants | 45 Participants | 65 Participants |
| Sex: Female, Male Male | 23 Participants | 46 Participants | 69 Participants |
| The Epworth Sleepiness Scale | 7.58 units on a scale | 9.09 units on a scale | 8.34 units on a scale |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 66 / 86 | 16 / 36 |
| other Total, other adverse events | 66 / 86 | 16 / 36 |
| serious Total, serious adverse events | 1 / 86 | 0 / 36 |
Outcome results
Primary
Obstructive Apnea Hypopnea Index
Efficacy measure to assess acute response to nasal steroids. Obstructive apnea hypopnea index (events per hour). Per inclusion/exclusion criteria the expected range for this study at baseline is between 2 and 30 events per hour. Please note that lower and upper ranges can be broader at the 3- and 12-month points. The obstructive apnea hypopnea index (OAHI) is the sum of obstructive apneas and hypopneas, and mixed apneas divided by the total hours of sleep. Hence, the unit used is events per hour. It ranges from 0 events per hour(meaning no obstructive apneas at all) until 400 events per hour approximately. Higher values indicate more severe obstructive sleep apnea or worse outcome.
Time frame: 3 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Nasal Steroids | Obstructive Apnea Hypopnea Index | 7.69 events per hour |
| Placebo | Obstructive Apnea Hypopnea Index | 6.33 events per hour |
Secondary
Behavior Rating Inventory of Executive Function (BRIEF)
Behavior Rating Inventory of Executive Function \[BRIEF\] Global Executive Composite T score, comprising summary measures of behavioral regulation and metacognition \[with mean scores of 50 and standard deviation of 10, with higher scores indicating worse functioning\]
Time frame: 12 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Nasal Steroids | Behavior Rating Inventory of Executive Function (BRIEF) | 47.42 T-Score |
| Placebo | Behavior Rating Inventory of Executive Function (BRIEF) | 49.5 T-Score |
Secondary
Child Behavior Checklist
The Child Behavior Checklist (CBCL), is a widely used and validated caregiver-completed survey of behavior competencies that yields standardized, age-adjusted scores on internalizing, externalizing and attentional behavior difficulties81, 82. All scores are T scores with a mean of 50 and standard deviation of 10 (higher scores indicate worse functioning).
Time frame: 12-Months
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Nasal Steroids | Child Behavior Checklist | Internalizing | 49.92 T-Score |
| Nasal Steroids | Child Behavior Checklist | Externalizing | 51.89 T-Score |
| Nasal Steroids | Child Behavior Checklist | Total Behavior Problems | 51.45 T-Score |
| Nasal Steroids | Child Behavior Checklist | Attention | 55.13 T-Score |
| Placebo | Child Behavior Checklist | Attention | 57.38 T-Score |
| Placebo | Child Behavior Checklist | Internalizing | 51.94 T-Score |
| Placebo | Child Behavior Checklist | Total Behavior Problems | 51.19 T-Score |
| Placebo | Child Behavior Checklist | Externalizing | 52 T-Score |
Secondary
Conners Abbreviated Symptom Questionnaire
A parent-rated measure of symptoms of attention problems, yielding T scores with a mean of 50 and a standard deviation of 10 (higher scores indicate worse functioning).
Time frame: 12 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Nasal Steroids | Conners Abbreviated Symptom Questionnaire | 5.62 T-Score |
| Placebo | Conners Abbreviated Symptom Questionnaire | 6.50 T-Score |
Secondary
Conners Continuous Performance Test (CPT)
The CPT is a performance measure of sustained attention that yields T scores with a mean of 50 and a standard deviation of 10 (higher scores indicate worse functioning)
Time frame: 12 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Nasal Steroids | Conners Continuous Performance Test (CPT) | 52.67 T-Score |
| Placebo | Conners Continuous Performance Test (CPT) | 52.92 T-Score |
Secondary
Nasal Obstruction Symptom Evaluation (NOSE)
Nasal Obstruction Symptom Evaluation (NOSE) scale, a validated scale of nasal obstructive symptoms. The scales ranges from 0-100 with higher values indicating worse nasal obstruction
Time frame: 12 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Nasal Steroids | Nasal Obstruction Symptom Evaluation (NOSE) | 3.66 score on a scale |
| Placebo | Nasal Obstruction Symptom Evaluation (NOSE) | 5.31 score on a scale |
Secondary
OAHI
Efficacy measure to assess duration of response to nasal steroids. Obstructive apnea hypopnea index (events per hour). Per inclusion/exclusion criteria the expected range for this study at baseline is between 2 and 30 events per hour. Please note that lower and upper ranges can be broader at the 3- and 12-month points.
Time frame: 12 months
Population: The obstructive apnea hypopnea index (OAHI) is the sum of obstructive apneas and hypopneas, and mixed apneas divided by the total hours of sleep. Hence, the unit used is events per hour. It ranges from 0 events per hour(meaning no obstructive apneas at all) until 400 events per hour approximately. Higher values indicate more severe obstructive sleep apnea or worse outcome.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Nasal Steroids | OAHI | 6.11 events per hour |
| Placebo | OAHI | 6.27 events per hour |
Secondary
Pediatric Quality of Life Inventory (PedsQL)
Pediatric Quality of Life Inventory (PedsQL), a well-validated, generic measure of global quality of life, in which scores range from 0 to 100, with higher scores indicating better quality of life
Time frame: 12 month
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Nasal Steroids | Pediatric Quality of Life Inventory (PedsQL) | 78.69 score on a scale |
| Placebo | Pediatric Quality of Life Inventory (PedsQL) | 73.67 score on a scale |
Secondary
Purdue Peg Board
The Purdue Peg Board is a widely used test of fine motor coordination, yields z-scores with a mean of 0 and a standard deviation of 1, with higher scores indicating better performance.
Time frame: 12 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Nasal Steroids | Purdue Peg Board | -1.12 z-Score |
| Placebo | Purdue Peg Board | -1.31 z-Score |
Secondary
The Epworth Sleepiness Scale
Epworth Sleepiness scale is a measure of sleepiness that ranges from 0-24, with higher values indicating sleepiness
Time frame: 12 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Nasal Steroids | The Epworth Sleepiness Scale | 7.68 score on a scale |
| Placebo | The Epworth Sleepiness Scale | 8.56 score on a scale |