Apnea Positive Pressure Long-Term Efficacy Study

Study Overview
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Brief Summary
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The purpose of this study is to determine the effectiveness of nasal continuous positive airway pressure (CPAP) therapy for the treatment of obstructive sleep apnea syndrome (OSAS).

Detailed Description
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BACKGROUND: Nasal CPAP therapy is in widespread use as the primary treatment for OSAS, a sleep-related breathing disorder affecting more than 15 million Americans. The therapeutic effectiveness of CPAP in providing significant, stable, and long-term neurocognitive or other functional benefits to patients with OSAS has not been systematically investigated. DESIGN NARRATIVE: The study is a randomized, blinded, sham-controlled, multi-center trial of CPAP therapy. The principal aims of the study are: 1) to assess the long-term effectiveness of CPAP therapy on neurocognitive function, mood, sleepiness, and quality of life by administering tests of these indices to subjects randomly assigned to active or sham CPAP; 2) to identify specific neurocognitive deficits associated with OSAS in a large, heterogeneous subject population; 3) to determine which deficits in neurocognitive function in OSAS subjects are reversible and most sensitive to the effects of CPAP; 4) to develop a composite multivariate outcome measure from the results of this study that can be used to assess the clinical effectiveness of CPAP in improving neurocognitive function, mood, sleepiness, and quality of life; and 5) to use functional magnetic resonance imaging to compare cortical activation before and after CPAP therapy, and to assess whether this change is associated with improvement in specific neurocognitive task performance. The primary endpoint of the study is the effect of six months of CPAP treatment on neurocognitive function. A total of 1100 subjects (550 per treatment group) will be enrolled from the patient populations at five sites (Stanford University; University of Arizona; Brigham and Women's Hospital; Massachusetts; St. Luke's Hospital, Missouri; St. Mary Medical Center, Washington).

Official Title
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APPLES: Apnea Positive Pressure Long-Term Efficacy Study

Conditions
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Lung Diseases, Sleep Apnea Syndromes, Sleep

Intervention / Treatment
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* Device: Active CPAP
* Device: Sham CPAP


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female adults age 18 years or older with a diagnosis of OSAS using clinical criteria defined by the study protocol Study participation may require seven or more laboratory visits over six months Exclusion Criteria: Prior treatment for OSAS with continuous positive airway pressure or surgery Potential sleep apnea complications that may affect the health or safety of the participant, including low blood oxygen, recent near-miss or prior automobile accident due to sleepiness, congestive heart failure, history of angina, coronary artery disease, myocardial infarction or stroke, cardiac rhythm disturbance, and chronic neurological disorders affecting neurocognitive abilities or daily function The use of hypnotics, anxiolytics, sedating antidepressants, anticonvulsants, sedating antihistamines, stimulants or other medications likely to affect neurocognitive function and/or alertness Respiratory disease requiring medications (unless on stable medications for 2 months) Cancer, unless in remission for greater than one year and not taking exclusionary medications Self-reported renal failure Pregnancy anytime during a subject's participation Psychiatric illness, as defined by a DSM-IV diagnosis, except for depression or mild anxiety Narcolepsy, idiopathic hypersomnolence, DSM-IV chronic insomnia, restless legs syndrome, or rapid eye movement (REM) behavior disorder Current use of diurnal or nocturnal supplemental oxygen Significant vision, hearing, or coordination problems Difficulty understanding or speaking English Currently working night or rotating shifts Consumption of more than 10 caffeinated beverages per day (approximately 1,000 mg per day) Smokers whose habit interferes with the overnight polysomnogram or with the battery of testing during the day Consumption of more than 2 alcoholic beverages per day Any illicit drug usage or marijuana usage more than once a week Any individual in the household currently on CPAP or on CPAP in the past A score of 26 or less on the Mini Mental State Examination (MMSE)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active CPAP<br>Active Continuous Positive Airway Pressure (CPAP) | Device: Active CPAP<br>* Nightly nasal continuous positive airway pressure (CPAP)<br>* Other names: Positive Pressure Respiration;|
| Placebo Comparator: Sham CPAP<br>Sham Continuous Positive Airway Pressure (CPAP) | Device: Sham CPAP<br>* Sham CPAP machine will be used for participants in the placebo group.<br>* Other names: Sham CPAP machine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of CPAP on Neurocognitive Function: E/F Function- SWMT-OMD | There are three primary measures of neurocognitive function measured for APPLES, each representing a different domain: Executive and Frontal-lobe (E/F) Function- Sustained Working Memory Test Overall Mid-Day Index (SWMT-OMD), Attention and Psychomotor (A/P) Function- Pathfinder Number Test Total Time (PFN-TOTL), and Learning and Memory (L/M) Function- Buschke Selective Reminding Test Sum Recall (BSRT-SR). This is domain #1: Executive and Frontal-lobe (E/F) Function- Sustained Working Memory Test Overall Mid-Day Index (SWMT-OMD) SWMT-OMD is a scaled score that indicates whether the participant scored lower or higher relative to baseline using standard deviation units. It is computed as the mean of three sub-scores, one based on working memory (WM) task performance (behavioral WM sub-score: speed, accuracy), and the other two on electroencephalogram (EEG) (cortical activation sub-score: neural workload, attentional effort during WM task; alertness sub-score: resting alertness). | 2 months and 6 months post intervention | 
| Effect of CPAP on Neurocognitive Function: A/P Function- PFN-TOTL | There are three primary measures of neurocognitive function measured for APPLES, each representing a different domain: Executive and Frontal-lobe (E/F) Function- Sustained Working Memory Test Overall Mid-Day Index (SWMT-OMD), Attention and Psychomotor (A/P) Function- Pathfinder Number Test Total Time (PFN-TOTL), and Learning and Memory (L/M) Function- Buschke Selective Reminding Test Sum Recall (BSRT-SR). This is domain #2: Attention and Psychomotor (A/P) Function- Pathfinder Number Test Total Time (PFN-TOTL) | Measured at diagnostic visit (baseline) and 2 months and 6 months post intervention | 
| Effect of CPAP on Neurocognitive Function: L/M Function- BSRT-SR | There are three primary measures of neurocognitive function measured for APPLES, each representing a different domain: Executive and Frontal-lobe (E/F) Function- Sustained Working Memory Test Overall Mid-Day Index (SWMT-OMD), Attention and Psychomotor (A/P) Function- Pathfinder Number Test Total Time (PFN-TOTL), and Learning and Memory (L/M) Function- Buschke Selective Reminding Test Sum Recall (BSRT-SR). This is domain #3: Learning and Memory (L/M) Function- Buschke Selective Reminding Test Sum Recall (BSRT-SR) | Measured at diagnostic visit (baseline) and 2 months and 6 months post intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Attention and Psychomotor (A/P) Function: Pathfinder Number- Reaction Time (PN-RT) | The APPLES a priori Secondary Neurocognitive Analysis Plan specified a dimension reduction method to reduce twelve secondary neurocognitive variables from three neurocognitive domains to seven variables from three neurocognitive domains. Three of the selected variables came from the domain of Attention and Psychomotor (A/P) Function: Pathfinder Number- Reaction Time (PN-RT), Psychomotor Vigilance Task- Median Reaction Time (PVT-MedRT), and PVT- Mean Slowest 10% of Reaction Times (PVT-Slo10%RT). These data are for variable #1: Pathfinder Number- Reaction Time (PN-RT) | 2 months and 6 months post intervention | 
| Attention and Psychomotor (A/P) Function: Psychomotor Vigilance Task- Median Reaction Time (PVT-MedRT) | The APPLES a priori Secondary Neurocognitive Analysis Plan specified a dimension reduction method to reduce twelve secondary neurocognitive variables from three neurocognitive domains to seven variables from three neurocognitive domains. Three of the selected variables came from the domain of Attention and Psychomotor (A/P) Function: Pathfinder Number- Reaction Time (PN-RT), Psychomotor Vigilance Task- Median Reaction Time (PVT-MedRT), and PVT- Mean Slowest 10% of Reaction Times (PVT-Slo10%RT). These data are for variable #2: Psychomotor Vigilance Task- Median Reaction Time (PVT-MedRT) | 2 months and 6 months post intervention | 
| Attention and Psychomotor (A/P) Function: PVT- Mean Slowest 10% of Reaction Times (PVT-Slo10%RT) | The APPLES a priori Secondary Neurocognitive Analysis Plan specified a dimension reduction method to reduce twelve secondary neurocognitive variables from three neurocognitive domains to seven variables from three neurocognitive domains. Three of the selected variables came from the domain of Attention and Psychomotor (A/P) Function: Pathfinder Number- Reaction Time (PN-RT), Psychomotor Vigilance Task- Median Reaction Time (PVT-MedRT), and PVT- Mean Slowest 10% of Reaction Times (PVT-Slo10%RT). These data are for variable #3: PVT- Mean Slowest 10% of Reaction Times (PVT-Slo10%RT) | 2 months and 6 months post intervention | 
| Learning and Memory (L/M) Function: Buschke Selective Reminding Test Delayed Recall- Total Recall (BSRTDR-TotRec) | The APPLES a priori Secondary Neurocognitive Analysis Plan specified a dimension reduction method to reduce twelve secondary neurocognitive variables from three neurocognitive domains to seven variables from three neurocognitive domains. One of the selected variables came from the domain of Learning and Memory (L/M) Function: Buschke Selective Reminding Test Delayed Recall- Total Recall (BSRTDR-TotRec). | 2 months and 6 months post intervention | 
| Executive and Frontal-Lobe (E/F) Function: Sustained Working Memory Test- Mid-day Behavioral Index (SWMT-BehMD) | The APPLES a priori Secondary Neurocognitive Analysis Plan specified a dimension reduction method to reduce twelve secondary neurocognitive variables from three neurocognitive domains to seven variables from three neurocognitive domains. Three of the selected variables came from the domain of Executive and Frontal-Lobe (E/F) Function: SWMT-BehMD, SWMT-ActMD, and SAT-D-NumRuCh. These data are for variable #1: Sustained Working Memory Test- Mid-day Behavioral Index (SWMT-BehMD) SWMT-BehMD is a scaled score that indicates whether the participant scored lower or higher relative to baseline using standard deviation units. It is computed as the difference from baseline relative to measures of working memory (WM) task performance accuracy (percent correct) and mean and standard deviation of reaction time (milliseconds). High-load WM tasks receive twice the weight of the low-load WM tasks. | 2 months and 6 months post intervention | 
| Executive and Frontal-Lobe (E/F) Function: SWMT- Mid-day Activation Index (SWMT-ActMD) | The APPLES a priori Secondary Neurocognitive Analysis Plan specified a dimension reduction method to reduce twelve secondary neurocognitive variables from three neurocognitive domains to seven variables from three neurocognitive domains. Three of the selected variables came from the domain of Executive and Frontal-Lobe (E/F) Function: SWMT-BehMD, SWMT-ActMD, and SAT-D-NumRuCh. These data are for variable #2: SWMT- Mid-day Activation Index (SWMT-ActMD) SWMT-ActMD is a scaled score that indicates whether the participant scored lower or higher relative to baseline (BL) using standard deviation units. It is computed as the difference from BL relative to EEG power spectral variables (decibels) measured during the easier vs. more difficult working memory (WM) tasks. A positive activation sub-score indicates a larger cortical neuronal population was recruited to perform the more difficult WM task relative to BL, while a negative score indicates a smaller population was recruited. | 2 months and 6 months post intervention | 
| Executive and Frontal-Lobe (E/F) Function: Shifting Attention Test Discovery Condition- Number of Rule Changes (SAT-D-NumRuCh) | The APPLES a priori Secondary Neurocognitive Analysis Plan specified a dimension reduction method to reduce twelve secondary neurocognitive variables from three neurocognitive domains to seven variables from three neurocognitive domains. Three of the selected variables came from the domain of Executive and Frontal-Lobe (E/F) Function: Sustained Working Memory Test- Mid-day Behavioral Index (SWMT-BehMD), SWMT- Mid-day Activation Index (SWMT-ActMD), and Shifting Attention Test Discovery Condition- Number of Rule Changes (SAT-D-NumRuCh). These data are for variable #3: Shifting Attention Test Discovery Condition- Number of Rule Changes (SAT-D-NumRuCh) | 2 months and 6 months post intervention | 
| Objective Sleepiness/Alertness: Maintenance of Wakefulness Test- Mean Sleep Latency (MWT-MSL) | Objective sleepiness/alertness was measured using the Maintenance of Wakefulness Test (MWT); the outcome variable was MWT Mean Sleep Latency (MWT-MSL). The MWT was administered using four twenty-minute trials where the participant was asked to sit in a chair, in a quiet and dimly lit room, with instructions to stay awake. Trials were performed at 10 AM, Noon, 2 PM and 4 PM. The mean sleep latency was calculated using the 4 trials from a given visit, and required that at least 3 of the 4 trials were performed and validated. | Measured at diagnostic visit (baseline) and 2 months and 6 months post intervention | 
| Subjective Sleepiness/Alertness: Epworth Sleepiness Scale- Total Score (ESS-TS) | Subjective sleepiness/alertness was measured using the Epworth Sleepiness Scale (ESS); the outcome variable was ESS Total Score (ESS-TS). The ESS is a validated questionnaire (8 questions) that ask the chances of dozing off in specific situations. Summing the scores produces a scaled total score between 0 and 24, with higher numbers indicating more subjective sleepiness. The ESS was administered the evening before the polysomnogram (PSG), or overnight sleep study. Data reported here include questionnaires collected at the DX, 2M, and 6M visits. | Measured at diagnostic visit (baseline) and 2 months and 6 months post intervention | 
| Mood |  | Measured at diagnostic visit (baseline) and 2 months and 6 months post intervention | 
| Quality of Life: Calgary Sleep Apnea Quality of Life Index- Total Score (SAQLI-TS) | Quality of life was measured using the Calgary Sleep Apnea Quality of Life Index (SAQLI), which is an interview-administered instrument with high internal consistency and reliability. The SAQLI was designed to assess components identified as important to patients including daily functioning, social interactions, emotional functioning, symptoms experienced, and treatment-related symptoms. Items are scored on a seven-point scale, averaged (taking into account treatment-related symptoms), to yield a composite score between 1 and 7, where higher scores represent better quality of life. | diagnostic visit (baseline) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Obstructive Sleep Apnea