Trial Outcomes & Findings for Apnea Positive Pressure Long-Term Efficacy Study (NCT NCT00051363)

Results Overview

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).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1105 participants

Primary outcome timeframe

2 months and 6 months post intervention

Results posted on

2018-11-28

Participant Flow

Participant milestones

Participant milestones
Measure	Active CPAP Active Continuous Positive Airway Pressure (CPAP) is widely used for the treatment of Obstructive Sleep Apnea (OSA)	Sham CPAP Sham Continuous Positive Airway Pressure (CPAP) has been modified to be sub-therapeutic, yet closely simulates an Active CPAP device.
Overall Study STARTED	558	547
Overall Study Randomized & Analyzed	556	542
Overall Study Completed 2M Visit On-Treatment	456	417
Overall Study Completed 2M Visit On-Study	468	432
Overall Study Completed 6M Visit On-Treatment	427	372
Overall Study Completed 6M Vist On-Study	443	403
Overall Study COMPLETED	443	403
Overall Study NOT COMPLETED	115	144

Reasons for withdrawal

Reasons for withdrawal
Measure	Active CPAP Active Continuous Positive Airway Pressure (CPAP) is widely used for the treatment of Obstructive Sleep Apnea (OSA)	Sham CPAP Sham Continuous Positive Airway Pressure (CPAP) has been modified to be sub-therapeutic, yet closely simulates an Active CPAP device.
Overall Study Dropped Post-Rand for Any Reason	102	126
Overall Study Disqualified Post-Rand for Any Reason	9	11
Overall Study Death	2	2
Overall Study Excluded Pre-Randomization	2	5

Baseline Characteristics

Apnea Positive Pressure Long-Term Efficacy Study

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Active CPAP n=556 Participants Active Continuous Positive Airway Pressure (CPAP) is widely used for the treatment of Obstructive Sleep Apnea (OSA)	Sham CPAP n=542 Participants Sham Continuous Positive Airway Pressure (CPAP) has been modified to be sub-therapeutic, yet closely simulates an Active CPAP device.	Total n=1098 Participants Total of all reporting groups
Age, Categorical <=18 years	1 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants
Age, Categorical Between 18 and 65 years	459 Participants n=93 Participants	464 Participants n=4 Participants	923 Participants n=27 Participants
Age, Categorical >=65 years	96 Participants n=93 Participants	78 Participants n=4 Participants	174 Participants n=27 Participants
Age, Continuous	52.2 years STANDARD_DEVIATION 12.2 • n=93 Participants	50.8 years STANDARD_DEVIATION 12.2 • n=4 Participants	51.5 years STANDARD_DEVIATION 12.2 • n=27 Participants
Sex: Female, Male Female	193 Participants n=93 Participants	186 Participants n=4 Participants	379 Participants n=27 Participants
Sex: Female, Male Male	363 Participants n=93 Participants	356 Participants n=4 Participants	719 Participants n=27 Participants
Region of Enrollment United States	556 participants n=93 Participants	542 participants n=4 Participants	1098 participants n=27 Participants

PRIMARY outcome

Timeframe: 2 months and 6 months post intervention

Population: Analyses conducted in accordance with the intention-to-treat principle.

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).

Outcome measures

Outcome measures
Measure	Active CPAP n=556 Participants Active Continuous Positive Airway Pressure (CPAP) is widely used for the treatment of Obstructive Sleep Apnea (OSA)	Sham CPAP n=542 Participants Sham Continuous Positive Airway Pressure (CPAP) has been modified to be sub-therapeutic, yet closely simulates an Active CPAP device.
Effect of CPAP on Neurocognitive Function: E/F Function- SWMT-OMD SWMT-OMD 2M	0.035 score on a scale Interval -0.019 to 0.09	-0.074 score on a scale Interval -0.133 to -0.015
Effect of CPAP on Neurocognitive Function: E/F Function- SWMT-OMD SWMT-OMD 6M	0.072 score on a scale Interval 0.012 to 0.132	0.018 score on a scale Interval -0.046 to 0.082

PRIMARY outcome

Timeframe: Measured at diagnostic visit (baseline) and 2 months and 6 months post intervention

Population: Analyses conducted in accordance with the intention-to-treat principle.

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)

Outcome measures

Outcome measures
Measure	Active CPAP n=556 Participants Active Continuous Positive Airway Pressure (CPAP) is widely used for the treatment of Obstructive Sleep Apnea (OSA)	Sham CPAP n=542 Participants Sham Continuous Positive Airway Pressure (CPAP) has been modified to be sub-therapeutic, yet closely simulates an Active CPAP device.
Effect of CPAP on Neurocognitive Function: A/P Function- PFN-TOTL PFN-TOTL 6M	23.48 seconds Interval 22.98 to 24.0	23.01 seconds Interval 22.51 to 23.54
Effect of CPAP on Neurocognitive Function: A/P Function- PFN-TOTL PFN-TOTL Dx	23.32 seconds Interval 22.88 to 23.78	23.08 seconds Interval 22.64 to 23.54
Effect of CPAP on Neurocognitive Function: A/P Function- PFN-TOTL PFN-TOTL 2M	23.56 seconds Interval 23.05 to 24.1	22.92 seconds Interval 22.41 to 23.45

PRIMARY outcome

Timeframe: Measured at diagnostic visit (baseline) and 2 months and 6 months post intervention

Population: Analyses conducted in accordance with the intention-to-treat principle.

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)

Outcome measures

Outcome measures
Measure	Active CPAP n=556 Participants Active Continuous Positive Airway Pressure (CPAP) is widely used for the treatment of Obstructive Sleep Apnea (OSA)	Sham CPAP n=542 Participants Sham Continuous Positive Airway Pressure (CPAP) has been modified to be sub-therapeutic, yet closely simulates an Active CPAP device.
Effect of CPAP on Neurocognitive Function: L/M Function- BSRT-SR BSRT-SR Dx	49.72 number of words recalled Interval 48.95 to 50.48	49.86 number of words recalled Interval 49.09 to 50.64
Effect of CPAP on Neurocognitive Function: L/M Function- BSRT-SR BSRT-SR 2M	52.32 number of words recalled Interval 51.5 to 53.13	51.95 number of words recalled Interval 51.1 to 52.8
Effect of CPAP on Neurocognitive Function: L/M Function- BSRT-SR BSRT-SR 6M	54.09 number of words recalled Interval 53.26 to 54.91	54.28 number of words recalled Interval 53.41 to 55.13

SECONDARY outcome

Timeframe: 2 months and 6 months post intervention

Population: Analyses conducted in accordance with the intention-to-treat principle. Analyses performed by OSA severity level categorized by apnea hypopnea index (AHI: # of respiratory events/hr of sleep) obtained via baseline polysomnography. Categories are: Mild OSA (AHI = 10-14.9; exclusion if AHI \<10), Moderate OSA (AHI = 15-29.9), Severe OSA (AHI \>=30).

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)

Outcome measures

Outcome measures
Measure	Active CPAP n=556 Participants Active Continuous Positive Airway Pressure (CPAP) is widely used for the treatment of Obstructive Sleep Apnea (OSA)	Sham CPAP n=542 Participants Sham Continuous Positive Airway Pressure (CPAP) has been modified to be sub-therapeutic, yet closely simulates an Active CPAP device.
Attention and Psychomotor (A/P) Function: Pathfinder Number- Reaction Time (PN-RT) 2M PN-RT Mild OSA	0.811 seconds Interval 0.785 to 0.839	0.801 seconds Interval 0.774 to 0.83
Attention and Psychomotor (A/P) Function: Pathfinder Number- Reaction Time (PN-RT) 6M PN-RT Mild OSA	0.811 seconds Interval 0.784 to 0.839	0.795 seconds Interval 0.767 to 0.826
Attention and Psychomotor (A/P) Function: Pathfinder Number- Reaction Time (PN-RT) 2M PN-RT Moderate OSA	0.831 seconds Interval 0.811 to 0.852	0.825 seconds Interval 0.806 to 0.845
Attention and Psychomotor (A/P) Function: Pathfinder Number- Reaction Time (PN-RT) 2M PN-RT Severe OSA	0.818 seconds Interval 0.802 to 0.834	0.812 seconds Interval 0.797 to 0.828
Attention and Psychomotor (A/P) Function: Pathfinder Number- Reaction Time (PN-RT) 6M PN-RT Moderate OSA	0.830 seconds Interval 0.808 to 0.853	0.819 seconds Interval 0.799 to 0.841
Attention and Psychomotor (A/P) Function: Pathfinder Number- Reaction Time (PN-RT) 6M PN-RT Severe OSA	0.817 seconds Interval 0.8 to 0.836	0.806 seconds Interval 0.79 to 0.823

SECONDARY outcome

Timeframe: 2 months and 6 months post intervention

Population: Analyses conducted in accordance with the intention-to-treat principle. Analyses performed by OSA severity level categorized by apnea hypopnea index (AHI: # of respiratory events/hr of sleep) obtained via baseline polysomnography. Categories are: Mild OSA (AHI = 10-14.9; exclusion if AHI \<10), Moderate OSA (AHI = 15-29.9), Severe OSA (AHI \>=30).

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)

Outcome measures

Outcome measures
Measure	Active CPAP n=556 Participants Active Continuous Positive Airway Pressure (CPAP) is widely used for the treatment of Obstructive Sleep Apnea (OSA)	Sham CPAP n=542 Participants Sham Continuous Positive Airway Pressure (CPAP) has been modified to be sub-therapeutic, yet closely simulates an Active CPAP device.
Attention and Psychomotor (A/P) Function: Psychomotor Vigilance Task- Median Reaction Time (PVT-MedRT) 2M PVT-MedRT Moderate OSA	248.68 milliseconds Interval 237.96 to 259.89	248.94 milliseconds Interval 237.99 to 260.4
Attention and Psychomotor (A/P) Function: Psychomotor Vigilance Task- Median Reaction Time (PVT-MedRT) 2M PVT-MedRT Severe OSA	243.25 milliseconds Interval 235.36 to 251.41	247.55 milliseconds Interval 238.79 to 256.62
Attention and Psychomotor (A/P) Function: Psychomotor Vigilance Task- Median Reaction Time (PVT-MedRT) 6M PVT-MedRT Mild OSA	245.23 milliseconds Interval 230.2 to 261.23	254.05 milliseconds Interval 237.26 to 272.03
Attention and Psychomotor (A/P) Function: Psychomotor Vigilance Task- Median Reaction Time (PVT-MedRT) 6M PVT-MedRT Moderate OSA	248.60 milliseconds Interval 236.74 to 261.04	249.10 milliseconds Interval 236.95 to 261.86
Attention and Psychomotor (A/P) Function: Psychomotor Vigilance Task- Median Reaction Time (PVT-MedRT) 2M PVT-MedRT Mild OSA	245.31 milliseconds Interval 230.94 to 260.58	253.89 milliseconds Interval 238.02 to 270.82
Attention and Psychomotor (A/P) Function: Psychomotor Vigilance Task- Median Reaction Time (PVT-MedRT) 6M PVT-MedRT Severe OSA	243.17 milliseconds Interval 234.05 to 252.64	247.70 milliseconds Interval 237.46 to 258.38

SECONDARY outcome

Timeframe: 2 months and 6 months post intervention

Population: Analyses conducted in accordance with the intention-to-treat principle. Analyses performed by OSA severity level categorized by apnea hypopnea index (AHI: # of respiratory events/hr of sleep) obtained via baseline polysomnography. Categories are: Mild OSA (AHI = 10-14.9; exclusion if AHI \<10), Moderate OSA (AHI = 15-29.9), Severe OSA (AHI \>=30).

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)

Outcome measures

Outcome measures
Measure	Active CPAP n=556 Participants Active Continuous Positive Airway Pressure (CPAP) is widely used for the treatment of Obstructive Sleep Apnea (OSA)	Sham CPAP n=542 Participants Sham Continuous Positive Airway Pressure (CPAP) has been modified to be sub-therapeutic, yet closely simulates an Active CPAP device.
Attention and Psychomotor (A/P) Function: PVT- Mean Slowest 10% of Reaction Times (PVT-Slo10%RT) 6M PVT-Slo10%RT Moderate OSA	406.17 milliseconds Interval 383.96 to 429.66	406.78 milliseconds Interval 385.63 to 429.09
Attention and Psychomotor (A/P) Function: PVT- Mean Slowest 10% of Reaction Times (PVT-Slo10%RT) 6M PVT-Slo10%RT Severe OSA	394.48 milliseconds Interval 377.66 to 412.05	405.04 milliseconds Interval 384.9 to 426.24
Attention and Psychomotor (A/P) Function: PVT- Mean Slowest 10% of Reaction Times (PVT-Slo10%RT) 2M PVT-Slo10%RT Mild OSA	403.00 milliseconds Interval 375.99 to 431.95	402.32 milliseconds Interval 376.77 to 429.62
Attention and Psychomotor (A/P) Function: PVT- Mean Slowest 10% of Reaction Times (PVT-Slo10%RT) 2M PVT-Slo10%RT Moderate OSA	412.44 milliseconds Interval 390.91 to 435.16	407.84 milliseconds Interval 387.67 to 429.06
Attention and Psychomotor (A/P) Function: PVT- Mean Slowest 10% of Reaction Times (PVT-Slo10%RT) 2M PVT-Slo10%RT Severe OSA	400.57 milliseconds Interval 384.51 to 417.3	406.11 milliseconds Interval 387.05 to 426.07
Attention and Psychomotor (A/P) Function: PVT- Mean Slowest 10% of Reaction Times (PVT-Slo10%RT) 6M PVT-Slo10%RT Mild OSA	396.87 milliseconds Interval 370.79 to 424.79	401.28 milliseconds Interval 375.51 to 428.82

SECONDARY outcome

Timeframe: 2 months and 6 months post intervention

Population: Analyses conducted in accordance with the intention-to-treat principle. Analyses performed by OSA severity level categorized by apnea hypopnea index (AHI: # of respiratory events/hr of sleep) obtained via baseline polysomnography. Categories are: Mild OSA (AHI = 10-14.9; exclusion if AHI \<10), Moderate OSA (AHI = 15-29.9), Severe OSA (AHI \>=30).

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).

Outcome measures

Outcome measures
Measure	Active CPAP n=556 Participants Active Continuous Positive Airway Pressure (CPAP) is widely used for the treatment of Obstructive Sleep Apnea (OSA)	Sham CPAP n=542 Participants Sham Continuous Positive Airway Pressure (CPAP) has been modified to be sub-therapeutic, yet closely simulates an Active CPAP device.
Learning and Memory (L/M) Function: Buschke Selective Reminding Test Delayed Recall- Total Recall (BSRTDR-TotRec) 2M BSRTDR-TotRec Mild OSA	8.54 number of words recalled Interval 7.99 to 9.1	8.20 number of words recalled Interval 7.53 to 8.87
Learning and Memory (L/M) Function: Buschke Selective Reminding Test Delayed Recall- Total Recall (BSRTDR-TotRec) 2M BSRTDR-TotRec Severe OSA	8.48 number of words recalled Interval 8.2 to 8.76	8.21 number of words recalled Interval 7.92 to 8.51
Learning and Memory (L/M) Function: Buschke Selective Reminding Test Delayed Recall- Total Recall (BSRTDR-TotRec) 6M BSRTDR-TotRec Severe OSA	8.87 number of words recalled Interval 8.58 to 9.16	8.75 number of words recalled Interval 8.48 to 9.01
Learning and Memory (L/M) Function: Buschke Selective Reminding Test Delayed Recall- Total Recall (BSRTDR-TotRec) 2M BSRTDR-TotRec Moderate OSA	8.49 number of words recalled Interval 8.13 to 8.85	8.22 number of words recalled Interval 7.82 to 8.62
Learning and Memory (L/M) Function: Buschke Selective Reminding Test Delayed Recall- Total Recall (BSRTDR-TotRec) 6M BSRTDR-TotRec Mild OSA	9.01 number of words recalled Interval 8.47 to 9.54	9.44 number of words recalled Interval 8.92 to 9.97
Learning and Memory (L/M) Function: Buschke Selective Reminding Test Delayed Recall- Total Recall (BSRTDR-TotRec) 6M BSRTDR-TotRec Moderate OSA	8.56 number of words recalled Interval 8.14 to 8.98	8.91 number of words recalled Interval 8.54 to 9.28

SECONDARY outcome

Timeframe: 2 months and 6 months post intervention

Population: Analyses conducted in accordance with the intention-to-treat principle. Analyses performed by OSA severity level categorized by apnea hypopnea index (AHI: # of respiratory events/hr of sleep) obtained via baseline polysomnography. Categories are: Mild OSA (AHI = 10-14.9; exclusion if AHI \<10), Moderate OSA (AHI = 15-29.9), Severe OSA (AHI \>=30).

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.

Outcome measures

Outcome measures
Measure	Active CPAP n=556 Participants Active Continuous Positive Airway Pressure (CPAP) is widely used for the treatment of Obstructive Sleep Apnea (OSA)	Sham CPAP n=542 Participants Sham Continuous Positive Airway Pressure (CPAP) has been modified to be sub-therapeutic, yet closely simulates an Active CPAP device.
Executive and Frontal-Lobe (E/F) Function: Sustained Working Memory Test- Mid-day Behavioral Index (SWMT-BehMD) 2M SWMT-BehMD Moderate OSA	0.137 score on a scale Interval 0.035 to 0.238	0.126 score on a scale Interval 0.007 to 0.245
Executive and Frontal-Lobe (E/F) Function: Sustained Working Memory Test- Mid-day Behavioral Index (SWMT-BehMD) 6M SWMT-BehMD Mild	0.143 score on a scale Interval -0.072 to 0.357	0.116 score on a scale Interval -0.123 to 0.356
Executive and Frontal-Lobe (E/F) Function: Sustained Working Memory Test- Mid-day Behavioral Index (SWMT-BehMD) 6M SWMT-BehMD Moderate OSA	0.194 score on a scale Interval 0.062 to 0.325	0.314 score on a scale Interval 0.191 to 0.437
Executive and Frontal-Lobe (E/F) Function: Sustained Working Memory Test- Mid-day Behavioral Index (SWMT-BehMD) 2M SWMT-BehMD Mild OSA	0.180 score on a scale Interval 0.006 to 0.355	0.104 score on a scale Interval -0.074 to 0.283
Executive and Frontal-Lobe (E/F) Function: Sustained Working Memory Test- Mid-day Behavioral Index (SWMT-BehMD) 2M SWMT-BehMD Severe OSA	0.205 score on a scale Interval 0.117 to 0.294	-0.011 score on a scale Interval -0.128 to 0.106
Executive and Frontal-Lobe (E/F) Function: Sustained Working Memory Test- Mid-day Behavioral Index (SWMT-BehMD) 6M SWMT-BehMD Severe OSA	0.321 score on a scale Interval 0.212 to 0.43	0.173 score on a scale Interval 0.052 to 0.295

SECONDARY outcome

Timeframe: 2 months and 6 months post intervention

Population: Analyses conducted in accordance with the intention-to-treat principle. Analyses performed by OSA severity level categorized by apnea hypopnea index (AHI: # of respiratory events/hr of sleep) obtained via baseline polysomnography. Categories are: Mild OSA (AHI = 10-14.9; exclusion if AHI \<10), Moderate OSA (AHI = 15-29.9), Severe OSA (AHI \>=30).

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.

Outcome measures

Outcome measures
Measure	Active CPAP n=556 Participants Active Continuous Positive Airway Pressure (CPAP) is widely used for the treatment of Obstructive Sleep Apnea (OSA)	Sham CPAP n=542 Participants Sham Continuous Positive Airway Pressure (CPAP) has been modified to be sub-therapeutic, yet closely simulates an Active CPAP device.
Executive and Frontal-Lobe (E/F) Function: SWMT- Mid-day Activation Index (SWMT-ActMD) 6M SWMT-ActMD Mild	0.157 score on a scale Interval -0.089 to 0.403	0.118 score on a scale Interval -0.117 to 0.353
Executive and Frontal-Lobe (E/F) Function: SWMT- Mid-day Activation Index (SWMT-ActMD) 2M SWMT-ActMD Mild	-0.050 score on a scale Interval -0.268 to 0.169	0.317 score on a scale Interval 0.031 to 0.603
Executive and Frontal-Lobe (E/F) Function: SWMT- Mid-day Activation Index (SWMT-ActMD) 2M SWMT-ActMD Moderate OSA	0.262 score on a scale Interval 0.084 to 0.44	0.170 score on a scale Interval 0.006 to 0.334
Executive and Frontal-Lobe (E/F) Function: SWMT- Mid-day Activation Index (SWMT-ActMD) 2M SWMT-ActMD Severe OSA	-0.003 score on a scale Interval -0.109 to 0.103	0.033 score on a scale Interval -0.093 to 0.159
Executive and Frontal-Lobe (E/F) Function: SWMT- Mid-day Activation Index (SWMT-ActMD) 6M SWMT-ActMD Moderate OSA	0.016 score on a scale Interval -0.131 to 0.162	0.014 score on a scale Interval -0.188 to 0.216
Executive and Frontal-Lobe (E/F) Function: SWMT- Mid-day Activation Index (SWMT-ActMD) 6M SWMT-ActMD Severe OSA	0.058 score on a scale Interval -0.068 to 0.185	0.123 score on a scale Interval -0.016 to 0.262

SECONDARY outcome

Timeframe: 2 months and 6 months post intervention

Population: Analyses conducted in accordance with the intention-to-treat principle. Analyses performed by OSA severity level categorized by apnea hypopnea index (AHI: # of respiratory events/hr of sleep) obtained via baseline polysomnography. Categories are: Mild OSA (AHI = 10-14.9; exclusion if AHI \<10), Moderate OSA (AHI = 15-29.9), Severe OSA (AHI \>=30).

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)

Outcome measures

Outcome measures
Measure	Active CPAP n=556 Participants Active Continuous Positive Airway Pressure (CPAP) is widely used for the treatment of Obstructive Sleep Apnea (OSA)	Sham CPAP n=542 Participants Sham Continuous Positive Airway Pressure (CPAP) has been modified to be sub-therapeutic, yet closely simulates an Active CPAP device.
Executive and Frontal-Lobe (E/F) Function: Shifting Attention Test Discovery Condition- Number of Rule Changes (SAT-D-NumRuCh) 6M SAT-D-NumRuCh Mild	0.897 number of rule changes (dichotomized) Interval 0.827 to 0.966	0.907 number of rule changes (dichotomized) Interval 0.832 to 0.982
Executive and Frontal-Lobe (E/F) Function: Shifting Attention Test Discovery Condition- Number of Rule Changes (SAT-D-NumRuCh) 2M SAT-D-NumRuCh Mild OSA	0.931 number of rule changes (dichotomized) Interval 0.885 to 0.977	0.929 number of rule changes (dichotomized) Interval 0.873 to 0.985
Executive and Frontal-Lobe (E/F) Function: Shifting Attention Test Discovery Condition- Number of Rule Changes (SAT-D-NumRuCh) 2M SAT-D-NumRuCh Moderate OSA	0.936 number of rule changes (dichotomized) Interval 0.904 to 0.968	0.951 number of rule changes (dichotomized) Interval 0.924 to 0.979
Executive and Frontal-Lobe (E/F) Function: Shifting Attention Test Discovery Condition- Number of Rule Changes (SAT-D-NumRuCh) 2M SAT-D-NumRuCh Severe OSA	0.952 number of rule changes (dichotomized) Interval 0.931 to 0.972	0.942 number of rule changes (dichotomized) Interval 0.918 to 0.967
Executive and Frontal-Lobe (E/F) Function: Shifting Attention Test Discovery Condition- Number of Rule Changes (SAT-D-NumRuCh) 6M SAT-D-NumRuCh Moderate OSA	0.903 number of rule changes (dichotomized) Interval 0.853 to 0.953	0.935 number of rule changes (dichotomized) Interval 0.896 to 0.975
Executive and Frontal-Lobe (E/F) Function: Shifting Attention Test Discovery Condition- Number of Rule Changes (SAT-D-NumRuCh) 6M SAT-D-NumRuCh Severe OSA	0.927 number of rule changes (dichotomized) Interval 0.894 to 0.959	0.924 number of rule changes (dichotomized) Interval 0.888 to 0.96

SECONDARY outcome

Timeframe: Measured at diagnostic visit (baseline) and 2 months and 6 months post intervention

Population: Analyses conducted in accordance with the intention-to-treat principle. Analyses performed by OSA severity level categorized by apnea hypopnea index (AHI: # of respiratory events/hr of sleep) obtained via baseline polysomnography. Categories are: Mild OSA (AHI = 10-14.9; exclusion if AHI \<10), Moderate OSA (AHI = 15-29.9), Severe OSA (AHI \>=30).

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.

Outcome measures

Outcome measures
Measure	Active CPAP n=556 Participants Active Continuous Positive Airway Pressure (CPAP) is widely used for the treatment of Obstructive Sleep Apnea (OSA)	Sham CPAP n=542 Participants Sham Continuous Positive Airway Pressure (CPAP) has been modified to be sub-therapeutic, yet closely simulates an Active CPAP device.
Objective Sleepiness/Alertness: Maintenance of Wakefulness Test- Mean Sleep Latency (MWT-MSL) DX MWT-MSL Mild OSA	17.51 minutes Standard Deviation 3.71	17.62 minutes Standard Deviation 3.38
Objective Sleepiness/Alertness: Maintenance of Wakefulness Test- Mean Sleep Latency (MWT-MSL) DX MWT-MSL	17.13 minutes Standard Deviation 3.86	16.95 minutes Standard Deviation 4.13
Objective Sleepiness/Alertness: Maintenance of Wakefulness Test- Mean Sleep Latency (MWT-MSL) DX MWT-MSL Moderate OSA	17.74 minutes Standard Deviation 3.50	17.76 minutes Standard Deviation 3.68
Objective Sleepiness/Alertness: Maintenance of Wakefulness Test- Mean Sleep Latency (MWT-MSL) DX MWT-MSL Severe OSA	16.68 minutes Standard Deviation 4.05	16.35 minutes Standard Deviation 4.43
Objective Sleepiness/Alertness: Maintenance of Wakefulness Test- Mean Sleep Latency (MWT-MSL) 2M MWT-MSL	17.96 minutes Standard Deviation 3.40	17.27 minutes Standard Deviation 3.89
Objective Sleepiness/Alertness: Maintenance of Wakefulness Test- Mean Sleep Latency (MWT-MSL) 2M MWT-MSL Mild OSA	17.52 minutes Standard Deviation 3.60	18.21 minutes Standard Deviation 2.94
Objective Sleepiness/Alertness: Maintenance of Wakefulness Test- Mean Sleep Latency (MWT-MSL) 2M MWT-MSL Moderate OSA	17.91 minutes Standard Deviation 3.39	18.14 minutes Standard Deviation 2.93
Objective Sleepiness/Alertness: Maintenance of Wakefulness Test- Mean Sleep Latency (MWT-MSL) 2M MWT-MSL Severe OSA	18.10 minutes Standard Deviation 3.35	16.63 minutes Standard Deviation 4.34
Objective Sleepiness/Alertness: Maintenance of Wakefulness Test- Mean Sleep Latency (MWT-MSL) 6M MWT-MSL	18.11 minutes Standard Deviation 3.27	17.34 minutes Standard Deviation 3.82
Objective Sleepiness/Alertness: Maintenance of Wakefulness Test- Mean Sleep Latency (MWT-MSL) 6M MWT-MSL Mild OSA	17.77 minutes Standard Deviation 4.00	17.89 minutes Standard Deviation 3.27
Objective Sleepiness/Alertness: Maintenance of Wakefulness Test- Mean Sleep Latency (MWT-MSL) 6M MWT-MSL Moderate OSA	17.90 minutes Standard Deviation 3.41	18.18 minutes Standard Deviation 3.27
Objective Sleepiness/Alertness: Maintenance of Wakefulness Test- Mean Sleep Latency (MWT-MSL) 6M MWT-MSL Severe OSA	18.30 minutes Standard Deviation 2.98	16.78 minutes Standard Deviation 4.10

SECONDARY outcome

Timeframe: Measured at diagnostic visit (baseline) and 2 months and 6 months post intervention

Population: Analyses conducted in accordance with the intention-to-treat principle. Analyses performed by OSA severity level categorized by apnea hypopnea index (AHI: # of respiratory events/hr of sleep) obtained via baseline polysomnography. Categories are: Mild OSA (AHI = 10-14.9; exclusion if AHI \<10), Moderate OSA (AHI = 15-29.9), Severe OSA (AHI \>=30).

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.

Outcome measures

Outcome measures
Measure	Active CPAP n=556 Participants Active Continuous Positive Airway Pressure (CPAP) is widely used for the treatment of Obstructive Sleep Apnea (OSA)	Sham CPAP n=542 Participants Sham Continuous Positive Airway Pressure (CPAP) has been modified to be sub-therapeutic, yet closely simulates an Active CPAP device.
Subjective Sleepiness/Alertness: Epworth Sleepiness Scale- Total Score (ESS-TS) DX ESS-TS Severe OSA	10.35 scores on a scale Standard Deviation 4.24	10.37 scores on a scale Standard Deviation 4.28
Subjective Sleepiness/Alertness: Epworth Sleepiness Scale- Total Score (ESS-TS) 6M ESS-TS	7.39 scores on a scale Standard Deviation 4.21	8.41 scores on a scale Standard Deviation 4.18
Subjective Sleepiness/Alertness: Epworth Sleepiness Scale- Total Score (ESS-TS) DX ESS-TS	10.07 scores on a scale Standard Deviation 4.26	10.09 scores on a scale Standard Deviation 4.39
Subjective Sleepiness/Alertness: Epworth Sleepiness Scale- Total Score (ESS-TS) DX ESS-TS Mild OSA	10.10 scores on a scale Standard Deviation 4.55	9.73 scores on a scale Standard Deviation 4.43
Subjective Sleepiness/Alertness: Epworth Sleepiness Scale- Total Score (ESS-TS) DX ESS-TS Moderate OSA	9.57 scores on a scale Standard Deviation 4.13	9.75 scores on a scale Standard Deviation 4.56
Subjective Sleepiness/Alertness: Epworth Sleepiness Scale- Total Score (ESS-TS) 2M ESS-TS	7.86 scores on a scale Standard Deviation 4.20	8.89 scores on a scale Standard Deviation 4.31
Subjective Sleepiness/Alertness: Epworth Sleepiness Scale- Total Score (ESS-TS) 2M ESS-TS Mild OSA	8.59 scores on a scale Standard Deviation 4.31	7.90 scores on a scale Standard Deviation 4.01
Subjective Sleepiness/Alertness: Epworth Sleepiness Scale- Total Score (ESS-TS) 2M ESS-TS Moderate OSA	7.25 scores on a scale Standard Deviation 3.89	8.39 scores on a scale Standard Deviation 4.29
Subjective Sleepiness/Alertness: Epworth Sleepiness Scale- Total Score (ESS-TS) 2M ESS-TS Severe OSA	8.00 scores on a scale Standard Deviation 4.31	9.34 scores on a scale Standard Deviation 4.34
Subjective Sleepiness/Alertness: Epworth Sleepiness Scale- Total Score (ESS-TS) 6M ESS-TS Mild OSA	8.37 scores on a scale Standard Deviation 4.64	7.64 scores on a scale Standard Deviation 3.98
Subjective Sleepiness/Alertness: Epworth Sleepiness Scale- Total Score (ESS-TS) 6M ESS-TS Moderate OSA	7.07 scores on a scale Standard Deviation 3.87	8.43 scores on a scale Standard Deviation 4.55
Subjective Sleepiness/Alertness: Epworth Sleepiness Scale- Total Score (ESS-TS) 6M ESS-TS Severe OSA	7.31 scores on a scale Standard Deviation 4.25	8.56 scores on a scale Standard Deviation 4.02

SECONDARY outcome

Timeframe: Measured at diagnostic visit (baseline) and 2 months and 6 months post intervention

Population: Mood was dropped as a secondary outcome measure for analysis by our Core Team.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: diagnostic visit (baseline)

Population: Analyses performed for group of participants with SAQLI data. Baseline demographics were generally similar (mean age, sex ratio, proportion of white participants, average body mass index), and participants in both groups had similar SAQLI scores at baseline, which are presented below.

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.

Outcome measures

Outcome measures
Measure	Active CPAP n=443 Participants Active Continuous Positive Airway Pressure (CPAP) is widely used for the treatment of Obstructive Sleep Apnea (OSA)	Sham CPAP n=402 Participants Sham Continuous Positive Airway Pressure (CPAP) has been modified to be sub-therapeutic, yet closely simulates an Active CPAP device.
Quality of Life: Calgary Sleep Apnea Quality of Life Index- Total Score (SAQLI-TS)	4.7 Units on a scale Standard Deviation 0.8	4.7 Units on a scale Standard Deviation 0.8

OTHER_PRE_SPECIFIED outcome

Timeframe: Measured at diagnostic visit (baseline) and 6 months post intervention

Population: fMRI was dropped as a secondary outcome measure for analysis by our Core Team.

Outcome measures

Outcome data not reported

Adverse Events

Active CPAP

Serious events: 32 serious events

Other events: 390 other events

Deaths: 0 deaths

Sham CPAP

Serious events: 31 serious events

Other events: 373 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Active CPAP n=556 participants at risk Active Continuous Positive Airway Pressure (CPAP) is widely used for the treatment of Obstructive Sleep Apnea (OSA)	Sham CPAP n=542 participants at risk Sham Continuous Positive Airway Pressure (CPAP) has been modified to be sub-therapeutic, yet closely simulates an Active CPAP device.
Cardiac disorders Cardiovascular	0.72% 4/556 • Number of events 4 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.	1.1% 6/542 • Number of events 7 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.
General disorders Motor Vehicle Accident (MVA)	0.00% 0/556 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.	0.00% 0/542 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.
General disorders Death	0.36% 2/556 • Number of events 2 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.	0.37% 2/542 • Number of events 2 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.
Skin and subcutaneous tissue disorders Dermatological	0.18% 1/556 • Number of events 1 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.	0.00% 0/542 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.
General disorders General	0.36% 2/556 • Number of events 2 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.	0.55% 3/542 • Number of events 3 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.
Renal and urinary disorders Genitourinary	0.00% 0/556 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.	0.74% 4/542 • Number of events 4 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.
Gastrointestinal disorders GI / Digestive	1.1% 6/556 • Number of events 6 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.	0.92% 5/542 • Number of events 5 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.
General disorders HEENT	0.18% 1/556 • Number of events 1 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.	0.18% 1/542 • Number of events 1 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.
Musculoskeletal and connective tissue disorders Musculoskeletal	2.3% 13/556 • Number of events 13 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.	0.92% 5/542 • Number of events 5 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.
General disorders Near-miss MVA	0.00% 0/556 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.	0.55% 3/542 • Number of events 3 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.
Nervous system disorders Neurological	0.54% 3/556 • Number of events 3 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.	0.00% 0/542 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.
General disorders Other accident	0.18% 1/556 • Number of events 1 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.	0.55% 3/542 • Number of events 3 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.
Psychiatric disorders Psychiatric	0.18% 1/556 • Number of events 1 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.	0.00% 0/542 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.
Respiratory, thoracic and mediastinal disorders Respiratory	0.18% 1/556 • Number of events 1 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.	0.55% 3/542 • Number of events 3 • Adverse event data were collected from participant enrollment though the end of study visit (6 months). The APPLES Data and Safety Monitoring Board (DSMB) indicated events should be reported by body systems/event categories; data are reported this way. All Serious Adverse Events (SAEs) and Adverse Events (AEs) were categorized into 17 body systems/event categories. Safety data were reviewed regularly by the APPLES DSMB; three categories were deemed most important for SAEs: Cardiovascular, MVA, and Death. Analyses were performed on post-randomization events.

Other adverse events

Additional Information

Deborah A. Nichols

Stanford University

Phone: 208-908-7364

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place