Down Syndrome, Obstructive Sleep Apnea
Conditions
Keywords
atomoxetine, oxybutynin
Brief summary
This is a randomized, double blind, cross-over study of the combination of atomoxetine and oxybutynin (ato-oxy) in children with DS and OSA documented by polysomnography (PSG). Participants will receive high dose ato-oxy for four weeks as well as low dose ato-oxy for four weeks in random order. During the high dose ato-oxy period, participants will take 5 mg oxybutynin and 0.5mg/kg/day (max 40 mg) atomoxetine nightly for one week. Atomoxetine dose will then be increased to 1.2 mg/kg/day (max 80 mg). During the low dose ato-oxy period, participants will take 5 mg oxybutynin and 0.5mg/kg/day (max 40 mg) atomoxetine. Dosing of the study treatment will occur approximately 30 minutes prior to bedtime. Participants who withdraw from the study will not be replaced. Study participants will undergo eligibility screening that will include an initial screening to determine whether non- PSG enrollment criteria are met, followed by a 1 night in-lab PSG and health-related quality of life assessment for participants who qualify based on non-PSG criteria. For participants who are eligible and enroll in the study, the screening PSG night will serve as the baseline measure for apnea hypopnea index (AHI) and other PSG endpoints. On the final night of dosing for both high dose ato-oxy and low-dose ato-oxy, participants will return for inpatient PSG and health-related quality of life assessment. The primary efficacy endpoint is the change in obstructive AHI from baseline (high dose ato-oxy vs. low dose ato-oxy).
Interventions
Low dose ato-oxy will include 0.5 mg/kg/day of atomoxetine (max 40 mg) in combination with 5 mg oxybutynin High dose ato-oxy will include 1.2 mg/kg/day atomoxetine (max 80 mg) and 5 mg oxybutynin
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
University of Arizona
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female participants between 6 to 17 years of age, inclusive, at the Screening Visit. Enrollment will be stratified to ensure equal representation of children age 6-12 and age 13-17. No more than 14 subjects will be randomized for each age group. 2. Known diagnosis of Down syndrome (trisomy 21, but not translocation or mosaicism)
Exclusion criteria
1. Hypoxemia independent of respiratory events on polysomnography (≥5 minutes with oxygen saturation \<90%) 2. Presence of central sleep apnea on polysomnography (central AHI ≥ 5) 3. Currently using and adherent to PAP therapy (\>4 hours per night for 70% of nights in the past 30 days based on device download or parent report) 4. MAO inhibitor use 5. Urinary retention 6. Prematurity \< 37 weeks estimated gestational age 7. Seizure disorder 8. Untreated or inadequately treated hypothyroidism 9. Significant traumatic brain injury 10. Congenital heart disease and not cleared to participate by the patient's cardiologist 11. History of current, untreated depression 12. History of liver disease 13. 3+ or greater tonsillar hypertrophy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Obstructive Apnea-hypopnea Index (oAHI) | four weeks | change in number of obstructive apneas and hypopneas per hour on polysomnography from baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Obstructive Sleep Apnea-18 Score (OSA-18) | four weeks | Change in OSA-18 (a measure of health-related quality of life) from baseline. The OSA-18 score ranges from 18 to 136, with lower scores indicating better health-related quality of life. |
| Arousal Index | four weeks | change in number of arousals per hour on polysomnography from baseline |
Other
| Measure | Time frame | Description |
|---|---|---|
| REM Sleep Percentage | four weeks | Change in REM sleep percentage on polysomnography from baseline |
| Pediatric Quality of Life Inventory (PedsQL) Total Score | four weeks | Change in PedsQL total score (a measure of health-related quality of life) from baseline. The PedsQL score ranges from 0-100, with higher scores indicating better health-related quality of life. |
| N3 Sleep Percentage | four weeks | Change in N3 sleep percentage on polysomnography from baseline |
| Caregiver Global Impression of Change | four weeks | Change in Caregiver Global Impression of Change from baseline. This will be assessed on a seven point scale answering the question: Since the start of this therapy, my child's overall status is: 1. Very much improved; 2. Much improved; 3. Minimally Improved; 4. No change; 5. Minimally worse; 6. Much worse or 7. Very much worse. |
| N1 Sleep Percentage | four weeks | Change in N1 sleep percentage on polysomnography from baseline |
Countries
United States
Participant flow
Pre-assignment details
Enrollment was only 15 randomized participants rather than planned 24 due to recruitment delays related to the COVID-19 pandemic. 22 participants were enrolled but 7 did not qualify for randomization. 4 did not meet the requirement for apnea-hypopnea index \>5 on their baseline polysomnogram, 1 had hypoxemia unrelated to OSA on their baseline polysomnogram, 1 could not tolerate polysomnogram and 1 participant became adherent to CPAP between consent and baseline polysomnogram.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Atomoxetine and oxybutynin (ato-oxy): Low dose ato-oxy will include 0.5 mg/kg/day of atomoxetine (max 40 mg) in combination with 5 mg oxybutynin High dose ato-oxy will include 1.2 mg/kg/day atomoxetine (max 80 mg) and 5 mg oxybutynin | 11 |
| Total | 11 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 10.4 years STANDARD_DEVIATION 4.1 |
| BMI percentile | 79 percentile STANDARD_DEVIATION 23 |
| Congenital heart disease | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Region of Enrollment United States | 11 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 14 | 0 / 14 |
| other Total, other adverse events | 8 / 14 | 8 / 14 |
| serious Total, serious adverse events | 1 / 14 | 0 / 14 |
Outcome results
Primary
Obstructive Apnea-hypopnea Index (oAHI)
change in number of obstructive apneas and hypopneas per hour on polysomnography from baseline
Time frame: four weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High Dose Ato-oxy | Obstructive Apnea-hypopnea Index (oAHI) | -3.79 events per hour | Standard Deviation 2.74 |
| Low Dose Ato-oxy | Obstructive Apnea-hypopnea Index (oAHI) | -3.51 events per hour | Standard Deviation 3.06 |
Secondary
Arousal Index
change in number of arousals per hour on polysomnography from baseline
Time frame: four weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High Dose Ato-oxy | Arousal Index | 0.68 arousals per hour | Standard Deviation 8.24 |
| Low Dose Ato-oxy | Arousal Index | 2.01 arousals per hour | Standard Deviation 5.15 |
Secondary
Obstructive Sleep Apnea-18 Score (OSA-18)
Change in OSA-18 (a measure of health-related quality of life) from baseline. The OSA-18 score ranges from 18 to 136, with lower scores indicating better health-related quality of life.
Time frame: four weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High Dose Ato-oxy | Obstructive Sleep Apnea-18 Score (OSA-18) | -6.00 score on a scale | Standard Deviation 21.2 |
| Low Dose Ato-oxy | Obstructive Sleep Apnea-18 Score (OSA-18) | -6.82 score on a scale | Standard Deviation 11.91 |
Other Pre-specified
Caregiver Global Impression of Change
Change in Caregiver Global Impression of Change from baseline. This will be assessed on a seven point scale answering the question: Since the start of this therapy, my child's overall status is: 1. Very much improved; 2. Much improved; 3. Minimally Improved; 4. No change; 5. Minimally worse; 6. Much worse or 7. Very much worse.
Time frame: four weeks
Population: Form not completed by one participant for high dose.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High Dose Ato-oxy | Caregiver Global Impression of Change | 3.70 score on a scale | Standard Deviation 0.95 |
| Low Dose Ato-oxy | Caregiver Global Impression of Change | 3.45 score on a scale | Standard Deviation 1.03 |
Other Pre-specified
N1 Sleep Percentage
Change in N1 sleep percentage on polysomnography from baseline
Time frame: four weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High Dose Ato-oxy | N1 Sleep Percentage | 0.45 percentage of N1 sleep | Standard Deviation 3.49 |
| Low Dose Ato-oxy | N1 Sleep Percentage | 0.40 percentage of N1 sleep | Standard Deviation 3.17 |
Other Pre-specified
N3 Sleep Percentage
Change in N3 sleep percentage on polysomnography from baseline
Time frame: four weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High Dose Ato-oxy | N3 Sleep Percentage | -0.73 percentage of N3 sleep | Standard Deviation 14.58 |
| Low Dose Ato-oxy | N3 Sleep Percentage | -4.29 percentage of N3 sleep | Standard Deviation 13.14 |
Other Pre-specified
Pediatric Quality of Life Inventory (PedsQL) Total Score
Change in PedsQL total score (a measure of health-related quality of life) from baseline. The PedsQL score ranges from 0-100, with higher scores indicating better health-related quality of life.
Time frame: four weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High Dose Ato-oxy | Pediatric Quality of Life Inventory (PedsQL) Total Score | 1.97 score on a scale | Standard Deviation 15.77 |
| Low Dose Ato-oxy | Pediatric Quality of Life Inventory (PedsQL) Total Score | 3.36 score on a scale | Standard Deviation 15.27 |
Other Pre-specified
REM Sleep Percentage
Change in REM sleep percentage on polysomnography from baseline
Time frame: four weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| High Dose Ato-oxy | REM Sleep Percentage | -2.16 percentage of REM sleep | Standard Deviation 10.16 |
| Low Dose Ato-oxy | REM Sleep Percentage | -1.41 percentage of REM sleep | Standard Deviation 8.89 |