Hypertension, Lung Diseases, Sleep Apnea Syndromes
Conditions
Brief summary
The purpose of this study is to determine whether functional status improves in individuals with milder obstructive sleep apnea (OSA) following continuous positive airway pressure (CPAP) treatment.
Detailed description
BACKGROUND: OSA is characterized as mild, moderate, or severe, according to the number of respiratory disturbances per hour of sleep (RDI), as defined by the American Academy of Sleep Medicine. CPAP is the primary treatment for sleep apnea. The column of pressure delivered to the upper airway by this device immediately eliminates the respiratory disturbances when it is applied. There is evidence from randomized controlled studies that CPAP also improves functional status, and the key manifestation of OSA, including excessive daytime sleepiness, in individuals with severe OSI (i.e., RDI greater than 30). However, there has been limited research exploring improvement in functional status in individuals with less severe OSA (i.e., those with mild OSA and RDI of 5-15 or moderate OSA and RDI of 16-30). The large placebo effect that has been reported in controlled studies of OSA-associated functional outcomes mandates the need for a placebo in studies evaluating the true impact of this treatment. Results from the three randomized controlled studies in milder OSA that have examined this issue have been equivocal, principally because of serious methodological limitations. It remains unclear whether CPAP treatment improves daily functioning in those with milder OSA (RDI 5-30). This is a critical issue as this level of disease severity represents the largest segment of OSA and comprises 15% of the U.S. population. DESIGN NARRATIVE: Using Granger's model of functional assessment, this study will examine whether functional status improves in participants with milder OSA following CPAP treatment. The study will employ a randomized, placebo-controlled, parallel study design, and will use a sham CPAP device as the placebo in participants with significant daytime sleepiness. The study will test the hypothesis that the change in functional status (measured by the Functional Outcomes of Sleep Questionnaire) after 8 weeks of treatment will be greater for participants treated with active CPAP compared to the placebo. Secondary aims of the study include examining whether CPAP also improves daytime sleepiness, and determining whether CPAP can reduce nocturnal blood pressure to lower the risk for stroke and hypertension linked to OSA.
Interventions
CPAP device used at night
DEVICESham CPAP device - CPAP device with pressure delivered <1 cm H20
Sham CPAP device used at night
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Respironics Sleep and Respiratory Foundation
Cephalon
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Newly diagnosed with OSA on overnight polysomnogram (PSG) with RDI between 5 and 30 * Score of greater than 11 on the Epworth Sleepiness Scale (ESS) on two administrations of the instrument (performed at prescreening and screening), each completed on a different day to avoid sporadic values and confirm the presence of excessive daytime sleepiness * Stable medical history and no change in medications, including hypertension medications, in the 3 months prior to study entry * Stable psychiatric history and no change in psychotropic medications in the 3 months prior to study entry * Has access to a telephone
Exclusion criteria
* Diagnosis of another sleep disorder in addition to OSA based on PSG, e.g., periodic limb movement disorder (greater than 10 limb movements per hour of sleep with arousal); central sleep apnea (greater than 5 or more central apneas); insomnia; sleep hypoventilation syndrome; or narcolepsy * Previous treatment for sleep apnea with nasal CPAP, oral appliance, home oxygen therapy, uvulopalatopharyngoplasty, tracheotomy, or other surgery for OSA * Oxygen or bi-level CPAP required for treatment of OSA * Unable to return for study instructions or follow-up testing * Medically unstable condition (e.g., heart attack, congestive heart failure, Cheyne-Stokes breathing, unstable angina, uncontrolled thyroid disease, unstable diabetes, depression or psychosis, ventricular arrhythmias, cirrhosis, or recently diagnosed cancer) in the 3 months prior to study entry * Regular use (greater than 3 times per week) of sedative, hypnotic, or alerting medications (such as Modafinil) in the 3 months prior to study entry * Chronic nasal congestion that would prevent the use of a nasal mask, in the 3 months prior to study entry * History of automobile accidents due to excessive daytime sleepiness * Employed in transportation-related safety sensitive occupation such as an airline pilot, truck driver, or train engineer * Night shift worker regularly experiencing jet lag, or a history of irregular work schedules in the 6 months prior to study entry * Regular use of alcohol as determined by answering yes to one or more of the questions on the CAGE questionnaire (i.e., alcohol dependent) * Recent or recurring history of substance abuse leading to tolerance or dependence * Pregnant; women must either be postmenopausal or confirmed not pregnant by a urine pregnancy test * Unable to perform study tests, e.g., inability to communicate verbally; inability to write and read in English; less than a 5th grade reading level (evaluated using Flesch-Kincaid assessment); visual impairment; hearing impairment; cognitive impairment (e.g., previous head injury); or upper extremity motor deficit (e.g., previous stroke or spinal cord injury) * Residing with an individual who is currently using CPAP treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Score of the Functional Outcomes of Sleep Questionnaire at Baseline and Week 8 Treatment | 8 weeks | The primary endpoint is change after 8 weeks of treatment from baseline value (controlling for baseline value) in the 30-item Functional Outcomes of Sleep Questionnaire (FOSQ) that will be used to test the primary study hypothesis that patients with milder OSA (RDI 5-30) on active treatment will demonstrate greater mean change for the Total score from baseline to 8 weeks treatment. The FOSQ is designed to assess the impact of excessive sleepiness on functional status. The instrument has established content validity, test-retest reliability (r= 0.91), and internal consistency (alpha = 0.96). The scale ranges from 5 - 20 with normal functional status being a value greater than 17. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean Arterial Daytime Pressure at Baseline and Week 8 Treatment | Measured at Baseline and Week 8 treatment in the ITT sample | Change in mean arterial pressure (MAP) value from baseline to 8 weeks treatment, controlling for baseline, measured by 48 hours ambulatory blood pressure device - Space Laboratories |
| Change in the Score From Baseline to 8 Weeks Treatment Measured by the Profile of Mood States | Measured at Baseline and Week 8 treatment in the ITT sample | Change in the score from baseline to 8 weeks treatment, controlling for baseline, in the POMS is a reliable and valid measure of mood states that consists of 65 adjectives on which subjects' rate themselves as they feel today using a five-point scale. There are six mood or affective states on this test derived through factor analysis: Tension-Anxiety (score range 0-36), Depression-Dejection (score range 0 - 60), Anger-Hostility (score range 0-48), Vigor-Activity (score range 0-32), Fatigue-Inertia (score range 0-28), and Confusion-Bewilderment (score range 0-28). There is also a summary Total Mood Disturbance (TMD) score that gives a Total estimate of affective state score range 0-200). Higher scores indicate greater disability. |
| Change in the Score From Baseline to 8 Weeks Treatment Epworth Sleepiness Scale | Measured at Baseline and Week 8 of treatment in ITT sample | Change in the score from baseline to 8 weeks treatment, controlling for baseline in the self-rated 8 item measure of daytime sleepiness with a range from 0 - 24. Lower values indicting less daytime sleepiness |
| Change in the Score From Baseline to 8 Weeks Treatment on the SF36 - Physical | Baseline and Week 8 of treatment in ITT sample. | Change in the score from baseline to 8 weeks treatment, controlling for baseline, in the SF-36 is a 36-item questionnaire that assesses eight health concepts: physical functioning, bodily pain, role limitations due to physical problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. Higher scores indicate greater disability with a range of scores from 0-100. |
| Change in the Score From Baseline to 8 Weeks Treatment SF-36 Mental Component | Baseline and after 8 weeks of treatment in ITT sample | Change in the score from baseline to 8 weeks treatment, controlling for baseline, in the SF-36 is a 36-item questionnaire that assesses eight health concepts: physical functioning, bodily pain, role limitations due to physical problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. Higher scores indicate greater disability with a range of scores from 0-100. |
| Change in the Number of Lapses From Baseline to 8 Weeks Treatment on the Psychomotor Vigilance Task (PVT) - Total Lapses in 20 Minute Test | Baseline and 8 weeks of treatment in the ITT sample | Change in the score from baseline to 8 weeks treatment, controlling for baseline, in the PVT is an objective assessment of sleepiness and measures decrements in neurobehavioral performance due to sleepiness, i.e., ability to sustain attention and respond in a timely manner to salient signals.(7) The PVT yields five highly informative metrics on the capacity for sustained attention and vigilance performance: frequency of lapses, duration of lapse domain, optimum response time, vigilance decrement function, false response frequency. We applied this conceptually valid, relatively short duration, reliable task with known psychometric properties and minimal practice/learning curves to document attentional lapses (response times \> 500 msec) in performance. |
Countries
Canada, United States
Participant flow
Recruitment details
Participants were recruited from the sleep disorders clinic from each of the 5 participating centers. Potential participants were approached by study staff at each site once their medical record indicated that they may be candidates for the study. Recruitment commenced 1-11-05 and ended 4-18-2008.
Participants by arm
| Arm | Count |
|---|---|
| Active CPAP CPAP device | 121 |
| Sham CPAP Sham CPAP device | 118 |
| Total | 239 |
Baseline characteristics
| Characteristic | Active CPAP | Sham CPAP | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 6 Participants | 11 Participants |
| Age, Categorical Between 18 and 65 years | 116 Participants | 112 Participants | 228 Participants |
| Region of Enrollment Canada | 53 participants | 50 participants | 103 participants |
| Region of Enrollment United States | 68 participants | 68 participants | 136 participants |
| Sex: Female, Male Female | 55 Participants | 44 Participants | 99 Participants |
| Sex: Female, Male Male | 66 Participants | 74 Participants | 140 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 93 / 121 | 94 / 118 |
| serious Total, serious adverse events | 6 / 121 | 11 / 118 |
Outcome results
Primary
Change in the Score of the Functional Outcomes of Sleep Questionnaire at Baseline and Week 8 Treatment
The primary endpoint is change after 8 weeks of treatment from baseline value (controlling for baseline value) in the 30-item Functional Outcomes of Sleep Questionnaire (FOSQ) that will be used to test the primary study hypothesis that patients with milder OSA (RDI 5-30) on active treatment will demonstrate greater mean change for the Total score from baseline to 8 weeks treatment. The FOSQ is designed to assess the impact of excessive sleepiness on functional status. The instrument has established content validity, test-retest reliability (r= 0.91), and internal consistency (alpha = 0.96). The scale ranges from 5 - 20 with normal functional status being a value greater than 17.
Time frame: 8 weeks
Population: Consented and randomized participants who completed the FOSQ with mild or moderate obstructive sleep apnea.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active CPAP | Change in the Score of the Functional Outcomes of Sleep Questionnaire at Baseline and Week 8 Treatment | 0.98 scores on a scale | Standard Deviation 2.89 |
| Sham CPAP | Change in the Score of the Functional Outcomes of Sleep Questionnaire at Baseline and Week 8 Treatment | -0.14 scores on a scale | Standard Deviation 2.61 |
Secondary
Change in Mean Arterial Daytime Pressure at Baseline and Week 8 Treatment
Change in mean arterial pressure (MAP) value from baseline to 8 weeks treatment, controlling for baseline, measured by 48 hours ambulatory blood pressure device - Space Laboratories
Time frame: Measured at Baseline and Week 8 treatment in the ITT sample
Population: Population who had data post-randomization following 8 wks. intervention - ITT analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active CPAP | Change in Mean Arterial Daytime Pressure at Baseline and Week 8 Treatment | 90.3 mmHg | Standard Deviation 7.6 |
| Sham CPAP | Change in Mean Arterial Daytime Pressure at Baseline and Week 8 Treatment | 92 mmHg | Standard Deviation 7.9 |
Comparison: Intent to Treat analysis with Last Observation Carried Forward.p-value: 0.0995% CI: [-3.8, 0.3]ANCOVA
Secondary
Change in the Number of Lapses From Baseline to 8 Weeks Treatment on the Psychomotor Vigilance Task (PVT) - Total Lapses in 20 Minute Test
Change in the score from baseline to 8 weeks treatment, controlling for baseline, in the PVT is an objective assessment of sleepiness and measures decrements in neurobehavioral performance due to sleepiness, i.e., ability to sustain attention and respond in a timely manner to salient signals.(7) The PVT yields five highly informative metrics on the capacity for sustained attention and vigilance performance: frequency of lapses, duration of lapse domain, optimum response time, vigilance decrement function, false response frequency. We applied this conceptually valid, relatively short duration, reliable task with known psychometric properties and minimal practice/learning curves to document attentional lapses (response times \> 500 msec) in performance.
Time frame: Baseline and 8 weeks of treatment in the ITT sample
Population: The Intent-to-Treat Sample includes all randomized patients receiving at least a 20 minute interval of Active during the post randomization treatment period and who had no clinically significant major violations of inclusion or exclusion criteria.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active CPAP | Change in the Number of Lapses From Baseline to 8 Weeks Treatment on the Psychomotor Vigilance Task (PVT) - Total Lapses in 20 Minute Test | -2.91 number on a scale | Standard Deviation 26.12 |
| Sham CPAP | Change in the Number of Lapses From Baseline to 8 Weeks Treatment on the Psychomotor Vigilance Task (PVT) - Total Lapses in 20 Minute Test | 2.99 number on a scale | Standard Deviation 21.54 |
Secondary
Change in the Score From Baseline to 8 Weeks Treatment Epworth Sleepiness Scale
Change in the score from baseline to 8 weeks treatment, controlling for baseline in the self-rated 8 item measure of daytime sleepiness with a range from 0 - 24. Lower values indicting less daytime sleepiness
Time frame: Measured at Baseline and Week 8 of treatment in ITT sample
Population: Participants randomized and who had post-treatment data in ITT analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active CPAP | Change in the Score From Baseline to 8 Weeks Treatment Epworth Sleepiness Scale | -2.58 scores on a scale | Standard Deviation 4.28 |
| Sham CPAP | Change in the Score From Baseline to 8 Weeks Treatment Epworth Sleepiness Scale | -0.54 scores on a scale | Standard Deviation 3.49 |
Secondary
Change in the Score From Baseline to 8 Weeks Treatment Measured by the Profile of Mood States
Change in the score from baseline to 8 weeks treatment, controlling for baseline, in the POMS is a reliable and valid measure of mood states that consists of 65 adjectives on which subjects' rate themselves as they feel today using a five-point scale. There are six mood or affective states on this test derived through factor analysis: Tension-Anxiety (score range 0-36), Depression-Dejection (score range 0 - 60), Anger-Hostility (score range 0-48), Vigor-Activity (score range 0-32), Fatigue-Inertia (score range 0-28), and Confusion-Bewilderment (score range 0-28). There is also a summary Total Mood Disturbance (TMD) score that gives a Total estimate of affective state score range 0-200). Higher scores indicate greater disability.
Time frame: Measured at Baseline and Week 8 treatment in the ITT sample
Population: Population who had data post-randomization following 8 wks. intervention - ITT analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active CPAP | Change in the Score From Baseline to 8 Weeks Treatment Measured by the Profile of Mood States | -10.2 scores on a scale | Standard Deviation 25.5 |
| Sham CPAP | Change in the Score From Baseline to 8 Weeks Treatment Measured by the Profile of Mood States | -0.5 scores on a scale | Standard Deviation 20.1 |
Secondary
Change in the Score From Baseline to 8 Weeks Treatment on the SF36 - Physical
Change in the score from baseline to 8 weeks treatment, controlling for baseline, in the SF-36 is a 36-item questionnaire that assesses eight health concepts: physical functioning, bodily pain, role limitations due to physical problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. Higher scores indicate greater disability with a range of scores from 0-100.
Time frame: Baseline and Week 8 of treatment in ITT sample.
Population: The Intent-to-Treat Sample includes all randomized patients exposed to CPAP or Sham treatment during the post randomization treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active CPAP | Change in the Score From Baseline to 8 Weeks Treatment on the SF36 - Physical | 3.92 scores on a scale | Standard Deviation 7.46 |
| Sham CPAP | Change in the Score From Baseline to 8 Weeks Treatment on the SF36 - Physical | -0.19 scores on a scale | Standard Deviation 6.99 |
Secondary
Change in the Score From Baseline to 8 Weeks Treatment SF-36 Mental Component
Change in the score from baseline to 8 weeks treatment, controlling for baseline, in the SF-36 is a 36-item questionnaire that assesses eight health concepts: physical functioning, bodily pain, role limitations due to physical problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. Higher scores indicate greater disability with a range of scores from 0-100.
Time frame: Baseline and after 8 weeks of treatment in ITT sample
Population: The Intent-to-Treat Sample includes all randomized patients exposed to CPAP or Sham treatment during the post randomization treatment period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active CPAP | Change in the Score From Baseline to 8 Weeks Treatment SF-36 Mental Component | 3.38 scores on a scale | Standard Deviation 9.83 |
| Sham CPAP | Change in the Score From Baseline to 8 Weeks Treatment SF-36 Mental Component | 2.00 scores on a scale | Standard Deviation 8.1 |