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| ID | Type | Description | Link |
|---|---|---|---|
| R61HL151254 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Heart, Lung, and Blood Institute (NHLBI) | NIH |
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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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| High dose ato-oxy | Active Comparator |
| |
| Low dose ato-oxy | Active Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Atomoxetine and oxybutynin (ato-oxy) | Drug | 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Obstructive Apnea-hypopnea Index (oAHI) | change in number of obstructive apneas and hypopneas per hour on polysomnography from baseline | four weeks |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | four weeks |
| Arousal Index |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | four weeks |
| Caregiver Global Impression of Change |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Daniel Combs, MD | University of Arizona | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Arizona | Tucson | Arizona | 85721 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37555595 | Derived | Combs D, Edgin J, Hsu CH, Bottrill K, Van Vorce H, Gerken B, Matloff D, La Rue S, Parthasarathy S. The combination of atomoxetine and oxybutynin for the treatment of obstructive sleep apnea in children with Down syndrome. J Clin Sleep Med. 2023 Dec 1;19(12):2065-2073. doi: 10.5664/jcsm.10764. |
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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.
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| ID | Title | Description |
|---|---|---|
| FG000 | High Dose Ato-oxy Then Low Dose Ato-oxy | 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 |
| FG001 | Low Dose Ato-oxy Then High Dose Ato-oxy | 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 |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention |
| |||||||||||||
| Second Intervention |
|
Only participants with complete data were included in analysis. One participant did not have usable data on their final sleep study and is not included in these results.
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| ID | Title | Description |
|---|---|---|
| BG000 | 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 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Obstructive Apnea-hypopnea Index (oAHI) | change in number of obstructive apneas and hypopneas per hour on polysomnography from baseline | Posted | Mean | Standard Deviation | events per hour | four weeks |
|
Adverse event data was collected throughout time on therapy (1 month each for high and low dose ato-oxy)
Adverse events were assessed via weekly phone calls while on medications
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | High Dose Ato-oxy | 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 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Respiratory failure and death | Respiratory, thoracic and mediastinal disorders | Systematic Assessment | One participant developed sepsis, respiratory failure and death while on high-dose ato-oxy. This appeared related to infectious cause and did not appear related to the study on DSMB review. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Fatigue | Psychiatric disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Daniel Combs, MD | University of Arizona | 520-626-7780 | combs89@arizona.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jan 14, 2022 | Mar 15, 2024 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D020181 | Sleep Apnea, Obstructive |
| D004314 | Down Syndrome |
| ID | Term |
|---|---|
| D012891 | Sleep Apnea Syndromes |
| D001049 | Apnea |
| D012120 | Respiration Disorders |
| D012140 | Respiratory Tract Diseases |
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| ID | Term |
|---|---|
| D000069445 | Atomoxetine Hydrochloride |
| C005419 | oxybutynin |
| ID | Term |
|---|---|
| D011437 | Propylamines |
| D000588 | Amines |
| D009930 | Organic Chemicals |
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change in number of arousals per hour on polysomnography from baseline |
| 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. |
| four weeks |
| N1 Sleep Percentage | Change in N1 sleep percentage on polysomnography from baseline | four weeks |
| REM Sleep Percentage | Change in REM sleep percentage on polysomnography from baseline | four weeks |
| N3 Sleep Percentage | Change in N3 sleep percentage on polysomnography from baseline | four weeks |
| NOT COMPLETED |
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| BMI percentile | Mean | Standard Deviation | percentile |
|
| Congenital heart disease | Count of Participants | Participants |
|
|
|
| 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. | Posted | Mean | Standard Deviation | score on a scale | four weeks |
|
|
|
| Secondary | Arousal Index | change in number of arousals per hour on polysomnography from baseline | Posted | Mean | Standard Deviation | arousals per hour | four weeks |
|
|
|
| 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. | Posted | Mean | Standard Deviation | score on a scale | four weeks |
|
|
|
| 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. | Form not completed by one participant for high dose. | Posted | Mean | Standard Deviation | score on a scale | four weeks |
|
|
|
| Other Pre-specified | N1 Sleep Percentage | Change in N1 sleep percentage on polysomnography from baseline | Posted | Mean | Standard Deviation | percentage of N1 sleep | four weeks |
|
|
|
| Other Pre-specified | REM Sleep Percentage | Change in REM sleep percentage on polysomnography from baseline | Posted | Mean | Standard Deviation | percentage of REM sleep | four weeks |
|
|
|
| Other Pre-specified | N3 Sleep Percentage | Change in N3 sleep percentage on polysomnography from baseline | Posted | Mean | Standard Deviation | percentage of N3 sleep | four weeks |
|
|
|
| 1 |
| 14 |
| 1 |
| 14 |
| 8 |
| 14 |
| EG001 | Low Dose Ato-oxy | 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 | 0 | 14 | 0 | 14 | 8 | 14 |
|
| Mood changes | Psychiatric disorders | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
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| Headaches | Nervous system disorders | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | Systematic Assessment |
|
| Decreased urinary frequency | Renal and urinary disorders | Systematic Assessment |
|
| Dry mouth | Gastrointestinal disorders | Systematic Assessment |
|
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| D020919 |
| Sleep Disorders, Intrinsic |
| D020920 | Dyssomnias |
| D012893 | Sleep Wake Disorders |
| D009422 | Nervous System Diseases |
| D008607 | Intellectual Disability |
| D019954 | Neurobehavioral Manifestations |
| D009461 | Neurologic Manifestations |
| D000015 | Abnormalities, Multiple |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D025063 | Chromosome Disorders |
| D030342 | Genetic Diseases, Inborn |