Lung DiseasesPhase 3APPLESNCT00051363

Apnea Positive Pressure Long-Term Efficacy Study

A Phase 3 study testing Active CPAP in people with Lung Diseases and Sleep Apnea Syndromes, run by Stanford University at 5 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

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). Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Lung Diseases, Sleep Apnea Syndromes, Sleep
What is being tested?: Active CPAP
Type of treatment: Medical device
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 1,105 participants
Where: 5 sitesUnited States
Study dates: Sep 2002to Sep 2008
Phase: Phase 3
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

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

Who cannot join

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

Show all 19Show fewer

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)

Trial locations and contacts

5 sites in 1 country.

City, postcode or hospital

5 sites in 1 country

United States5 sites

Brigham & Women's Hospital
Boston, Massachusetts, 02459
St. Luke's Hospital
Chesterfield, Missouri, 63017
Stanford University School of Medicine
Palo Alto, California, 94305
University of Arizona AHSC
Tucson, Arizona, 85724
St. Mary Medical Center
Walla Walla, Washington, 99362

Other trials in United States

About this study

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

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).

Read the detailed description

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).

Conditions: Lung Diseases, Sleep Apnea Syndromes, Sleep
Being tested: Active CPAP, Sham CPAP
Keywords: Obstructive Sleep Apnea
Medical subject headings: Lung Diseases, Sleep Apnea Syndromes, Sleep Apnea, Obstructive

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Active CPAPDevice
Also called Positive Pressure Respiration
Nightly nasal continuous positive airway pressure (CPAP)
Sham CPAPDevice
Also called Sham CPAP machine
Sham CPAP machine will be used for participants in the placebo group.

Study groups in NCT00051363
Study group	Role	What they receive
Active CPAP	Active comparator	Active Continuous Positive Airway Pressure (CPAP) Receives: Device: Active CPAP
Sham CPAP	Placebo comparator	Sham Continuous Positive Airway Pressure (CPAP) Receives: Device: Sham CPAP

What is being measured

The primary outcome is the main question the study is designed to answer.

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

Secondary outcomes (11)

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Sep 2002Sep 2008

First posted13 Jan 2003 (estimated)
Study startSep 2002
Primary completionAug 2008
Study completionSep 2008

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (22)Papers the sponsor has linked to this study.
Other trials for Lung DiseasesStudies of the same condition, open and under way.
More trials run by Stanford UniversityThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 1,105 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00051363
Sponsor's protocol ID: 150
Other IDs: U01HL068060
Acronym: APPLES
Status last verified: Nov 2018
First submitted: 9 Jan 2003
Last updated: 28 Nov 2018
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
Individual data sharing: Yes: Only in de-identified format to researchers

Publications

Kushida CA, Nichols DA, Quan SF, Goodwin JL, White DP, Gottlieb DJ, Walsh JK, Schweitzer PK, Guilleminault C, Simon RD, Leary EB, Hyde PR, Holmes TH, Bloch DA, Green S, McEvoy LK, Gevins A, Dement WC. The Apnea Positive Pressure Long-term Efficacy Study (APPLES): rationale, design, methods, and procedures. J Clin Sleep Med. 2006 Jul 15;2(3):288-300.
PubMed 17561541
Holmes TH, Nichols DA, Thomander D, Kushida CA. A method for estimating normative distributions for study-specific populations of clinical trials. Contemp Clin Trials. 2012 Mar;33(2):445-9. doi: 10.1016/j.cct.2011.11.014. Epub 2011 Nov 25.
PubMed 22138103
Gevins A, Smith ME, McEvoy LK, Ilan AB, Chan CS, Jiang A, Sam-Vargas L, Abraham G. A cognitive and neurophysiological test of change from an individual's baseline. Clin Neurophysiol. 2011 Jan;122(1):114-20. doi: 10.1016/j.clinph.2010.06.010. Epub 2010 Jul 8.
PubMed 20619727
Quan SF, Chan CS, Dement WC, Gevins A, Goodwin JL, Gottlieb DJ, Green S, Guilleminault C, Hirshkowitz M, Hyde PR, Kay GG, Leary EB, Nichols DA, Schweitzer PK, Simon RD, Walsh JK, Kushida CA. The association between obstructive sleep apnea and neurocognitive performance--the Apnea Positive Pressure Long-term Efficacy Study (APPLES). Sleep. 2011 Mar 1;34(3):303-314B. doi: 10.1093/sleep/34.3.303.
PubMed 21358847
Kushida CA, Nichols DA, Holmes TH, Quan SF, Walsh JK, Gottlieb DJ, Simon RD Jr, Guilleminault C, White DP, Goodwin JL, Schweitzer PK, Leary EB, Hyde PR, Hirshkowitz M, Green S, McEvoy LK, Chan C, Gevins A, Kay GG, Bloch DA, Crabtree T, Dement WC. Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: The Apnea Positive Pressure Long-term Efficacy Study (APPLES). Sleep. 2012 Dec 1;35(12):1593-602. doi: 10.5665/sleep.2226.
PubMed 23204602
Vasquez MM, Goodwin JL, Drescher AA, Smith TW, Quan SF. Associations of dietary intake and physical activity with sleep disordered breathing in the Apnea Positive Pressure Long-Term Efficacy Study (APPLES). J Clin Sleep Med. 2008 Oct 15;4(5):411-8.
PubMed 18853696
Quan SF, Budhiraja R, Clarke DP, Goodwin JL, Gottlieb DJ, Nichols DA, Simon RD, Smith TW, Walsh JK, Kushida CA. Impact of treatment with continuous positive airway pressure (CPAP) on weight in obstructive sleep apnea. J Clin Sleep Med. 2013 Oct 15;9(10):989-93. doi: 10.5664/jcsm.3064.
PubMed 24127141
Batool-Anwar S, Goodwin JL, Drescher AA, Baldwin CM, Simon RD, Smith TW, Quan SF. Impact of CPAP on activity patterns and diet in patients with obstructive sleep apnea (OSA). J Clin Sleep Med. 2014 May 15;10(5):465-72. doi: 10.5664/jcsm.3686.
PubMed 24910546
Quan SF, Budhiraja R, Batool-Anwar S, Gottlieb DJ, Eichling P, Patel S, Shen W, Walsh JK, Kushida CA. Lack of Impact of Mild Obstructive Sleep Apnea on Sleepiness, Mood and Quality of Life. Southwest J Pulm Crit Care. 2014;9(1):44-56. doi: 10.13175/swjpcc082-14.
PubMed 25232509
Quan SF, Budhiraja R, Clarke DP, Goodwin JL, Gottlieb DJ, Nichols DA, Simon RD, Smith TW, Walsh JK, Kushida CA, Phillips B. You still need more than CPAP for OSA patients to lose weight. J Clin Sleep Med. 2014 Mar 15;10(3):349. doi: 10.5664/jcsm.3552. No abstract available.
PubMed 24634638
Prilipko O, Huynh N, Thomason ME, Kushida CA, Guilleminault C. An fMRI study of cerebrovascular reactivity and perfusion in obstructive sleep apnea patients before and after CPAP treatment. Sleep Med. 2014 Aug;15(8):892-8. doi: 10.1016/j.sleep.2014.04.004. Epub 2014 May 4.
PubMed 24916094
Huynh NT, Prilipko O, Kushida CA, Guilleminault C. Volumetric Brain Morphometry Changes in Patients with Obstructive Sleep Apnea Syndrome: Effects of CPAP Treatment and Literature Review. Front Neurol. 2014 Apr 29;5:58. doi: 10.3389/fneur.2014.00058. eCollection 2014.
PubMed 24808886
Prilipko O, Huynh N, Schwartz S, Tantrakul V, Kushida C, Paiva T, Guilleminault C. The effects of CPAP treatment on task positive and default mode networks in obstructive sleep apnea patients: an fMRI study. PLoS One. 2012;7(12):e47433. doi: 10.1371/journal.pone.0047433. Epub 2012 Dec 5.
PubMed 23227139
Prilipko O, Huynh N, Schwartz S, Tantrakul V, Kim JH, Peralta AR, Kushida C, Paiva T, Guilleminault C. Task positive and default mode networks during a parametric working memory task in obstructive sleep apnea patients and healthy controls. Sleep. 2011 Mar 1;34(3):293-301A. doi: 10.1093/sleep/34.3.293.
PubMed 21358846
Budhiraja R, Kushida CA, Nichols DA, Walsh JK, Simon RD, Gottlieb DJ, Quan SF. Impact of Randomization, Clinic Visits, and Medical and Psychiatric Cormorbidities on Continuous Positive Airway Pressure Adherence in Obstructive Sleep Apnea. J Clin Sleep Med. 2016 Mar;12(3):333-41. doi: 10.5664/jcsm.5578.
PubMed 26518698

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

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Study at a glance

From the registry record, last updated by the sponsor on 28 Nov 2018. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: APPLES: Apnea Positive Pressure Long-Term Efficacy Study
ClinicalTrials.gov ID: NCT00051363
Acronym / sponsor ID: APPLES / 150
Conditions: Lung Diseases, Sleep Apnea Syndromes, Sleep
Keywords: Obstructive Sleep Apnea
Phase: Phase 3
Study type: Interventional
Recruitment status: Completed
Enrolment: 1,105 participants (actual)
Lead sponsor: Stanford UniversityUniversity, hospital or other
Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
Study start: Sep 2002
Primary completion: Aug 2008 (actual)
Study completion: Sep 2008 (actual)
First posted: 13 Jan 2003 (estimated)
Results: Posted 30 Nov 2016

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

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

BACKGROUND:

DESIGN NARRATIVE:

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 2

Arm	Type	Receives
Active CPAP	Active comparator	Device: Active CPAPActive Continuous Positive Airway Pressure (CPAP)
Sham CPAP	Placebo comparator	Device: Sham CPAPSham Continuous Positive Airway Pressure (CPAP)

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (2 listed)

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

Key exclusion criteria (19 listed)

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

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
Active CPAPAlso: Positive Pressure RespirationNightly nasal continuous positive airway pressure (CPAP)	Device	Active CPAP
Sham CPAPAlso: Sham CPAP machineSham CPAP machine will be used for participants in the placebo group.	Device	Sham CPAP

Primary outcome

Effect of CPAP on Neurocognitive Function: E/F Function- SWMT-OMD
Time frame: 2 months and 6 months post intervention
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).
Effect of CPAP on Neurocognitive Function: A/P Function- PFN-TOTL
Time frame: Measured at diagnostic visit (baseline) and 2 months and 6 months post intervention
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)
Effect of CPAP on Neurocognitive Function: L/M Function- BSRT-SR
Time frame: Measured at diagnostic visit (baseline) and 2 months and 6 months post intervention
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)

11 secondary outcomes

Attention and Psychomotor (A/P) Function: Pathfinder Number- Reaction Time (PN-RT)
Time frame: 2 months and 6 months post intervention
Attention and Psychomotor (A/P) Function: Psychomotor Vigilance Task- Median Reaction Time (PVT-MedRT)
Time frame: 2 months and 6 months post intervention
Attention and Psychomotor (A/P) Function: PVT- Mean Slowest 10% of Reaction Times (PVT-Slo10%RT)
Time frame: 2 months and 6 months post intervention
Learning and Memory (L/M) Function: Buschke Selective Reminding Test Delayed Recall- Total Recall (BSRTDR-TotRec)
Time frame: 2 months and 6 months post intervention
Executive and Frontal-Lobe (E/F) Function: Sustained Working Memory Test- Mid-day Behavioral Index (SWMT-BehMD)
Time frame: 2 months and 6 months post intervention
Executive and Frontal-Lobe (E/F) Function: SWMT- Mid-day Activation Index (SWMT-ActMD)
Time frame: 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)
Time frame: 2 months and 6 months post intervention
Objective Sleepiness/Alertness: Maintenance of Wakefulness Test- Mean Sleep Latency (MWT-MSL)
Time frame: Measured at diagnostic visit (baseline) and 2 months and 6 months post intervention
Subjective Sleepiness/Alertness: Epworth Sleepiness Scale- Total Score (ESS-TS)
Time frame: Measured at diagnostic visit (baseline) and 2 months and 6 months post intervention
Mood
Time frame: 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)
Time frame: diagnostic visit (baseline)

Results and safety

Results posted to the registry on 30 Nov 2016, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Active CPAP	558	443
Sham CPAP	547	403

Primary outcome: Effect of CPAP on Neurocognitive Function: E/F Function- SWMT-OMD

Time frame: 2 months and 6 months post intervention. Mean (95% Confidence Interval). Unit: score on a scale

Measure	Active CPAP n = 556	Sham CPAP n = 542
SWMT-OMD 2M	0.035 (-0.019 to 0.090)	-0.074 (-0.133 to -0.015)
SWMT-OMD 6M	0.072 (0.012 to 0.132)	0.018 (-0.046 to 0.082)

Active CPAP vs Sham CPAP: p = 0.0074, Regression, Linear
Active CPAP vs Sham CPAP: p = 0.2254, Regression, Linear

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

Primary outcome: Effect of CPAP on Neurocognitive Function: A/P Function- PFN-TOTL

Time frame: Measured at diagnostic visit (baseline) and 2 months and 6 months post intervention. Mean (95% Confidence Interval). Unit: seconds

Measure	Active CPAP n = 556	Sham CPAP n = 542
PFN-TOTL Dx	23.32 (22.88 to 23.78)	23.08 (22.64 to 23.54)
PFN-TOTL 2M	23.56 (23.05 to 24.10)	22.92 (22.41 to 23.45)
PFN-TOTL 6M	23.48 (22.98 to 24.00)	23.01 (22.51 to 23.54)

Active CPAP vs Sham CPAP: p = 0.4538, Parametric survival analysis
Active CPAP vs Sham CPAP: p = 0.0860, Parametric survival analysis
Active CPAP vs Sham CPAP: p = 0.2103, Parametric survival analysis

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

Primary outcome: Effect of CPAP on Neurocognitive Function: L/M Function- BSRT-SR

Time frame: Measured at diagnostic visit (baseline) and 2 months and 6 months post intervention. Mean (95% Confidence Interval). Unit: number of words recalled

Measure	Active CPAP n = 556	Sham CPAP n = 542
BSRT-SR Dx	49.72 (48.95 to 50.48)	49.86 (49.09 to 50.64)
BSRT-SR 2M	52.32 (51.50 to 53.13)	51.95 (51.10 to 52.80)
BSRT-SR 6M	54.09 (53.26 to 54.91)	54.28 (53.41 to 55.13)

Active CPAP vs Sham CPAP: p = 0.7936, Regression, Linear
Active CPAP vs Sham CPAP: p = 0.5444, Regression, Linear
Active CPAP vs Sham CPAP: p = 0.7569, Regression, Linear

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

11 secondary outcomes are reported in the full results.

Adverse events

Time frame: 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.. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Active CPAP	32 of 556 (5.8%)	390 of 556 (70.1%)	Not reported
Sham CPAP	31 of 542 (5.7%)	373 of 542 (68.8%)	Not reported

Limitations and caveats (from the sponsor): There are study sample limitations because although participants with severe OSA were included, those who had the lowest oxygen saturation, a history of sleepiness-related accidents, or major cardiovascular comorbidities were excluded.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 28 Nov 2018.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Background: PubMed 17561541Kushida CA, Nichols DA, Quan SF, Goodwin JL, White DP, Gottlieb DJ, Walsh JK, Schweitzer PK, Guilleminault C, Simon RD, Leary EB, Hyde PR, Holmes TH, Bloch DA, Green S, McEvoy LK, Gevins A, Dement WC. The Apnea Positive Pressure Long-term Efficacy Study (APPLES): rationale, design, methods, and procedures. J Clin Sleep Med. 2006 Jul 15;2(3):288-300.
Background: PubMed 22138103Holmes TH, Nichols DA, Thomander D, Kushida CA. A method for estimating normative distributions for study-specific populations of clinical trials. Contemp Clin Trials. 2012 Mar;33(2):445-9. doi: 10.1016/j.cct.2011.11.014. Epub 2011 Nov 25.
Background: PubMed 20619727Gevins A, Smith ME, McEvoy LK, Ilan AB, Chan CS, Jiang A, Sam-Vargas L, Abraham G. A cognitive and neurophysiological test of change from an individual's baseline. Clin Neurophysiol. 2011 Jan;122(1):114-20. doi: 10.1016/j.clinph.2010.06.010. Epub 2010 Jul 8.
Results publication: PubMed 21358847Quan SF, Chan CS, Dement WC, Gevins A, Goodwin JL, Gottlieb DJ, Green S, Guilleminault C, Hirshkowitz M, Hyde PR, Kay GG, Leary EB, Nichols DA, Schweitzer PK, Simon RD, Walsh JK, Kushida CA. The association between obstructive sleep apnea and neurocognitive performance--the Apnea Positive Pressure Long-term Efficacy Study (APPLES). Sleep. 2011 Mar 1;34(3):303-314B. doi: 10.1093/sleep/34.3.303.
Results publication: PubMed 23204602Kushida CA, Nichols DA, Holmes TH, Quan SF, Walsh JK, Gottlieb DJ, Simon RD Jr, Guilleminault C, White DP, Goodwin JL, Schweitzer PK, Leary EB, Hyde PR, Hirshkowitz M, Green S, McEvoy LK, Chan C, Gevins A, Kay GG, Bloch DA, Crabtree T, Dement WC. Effects of continuous positive airway pressure on neurocognitive function in obstructive sleep apnea patients: The Apnea Positive Pressure Long-term Efficacy Study (APPLES). Sleep. 2012 Dec 1;35(12):1593-602. doi: 10.5665/sleep.2226.
Results publication: PubMed 18853696Vasquez MM, Goodwin JL, Drescher AA, Smith TW, Quan SF. Associations of dietary intake and physical activity with sleep disordered breathing in the Apnea Positive Pressure Long-Term Efficacy Study (APPLES). J Clin Sleep Med. 2008 Oct 15;4(5):411-8.
Results publication: PubMed 24127141Quan SF, Budhiraja R, Clarke DP, Goodwin JL, Gottlieb DJ, Nichols DA, Simon RD, Smith TW, Walsh JK, Kushida CA. Impact of treatment with continuous positive airway pressure (CPAP) on weight in obstructive sleep apnea. J Clin Sleep Med. 2013 Oct 15;9(10):989-93. doi: 10.5664/jcsm.3064.
Results publication: PubMed 24910546Batool-Anwar S, Goodwin JL, Drescher AA, Baldwin CM, Simon RD, Smith TW, Quan SF. Impact of CPAP on activity patterns and diet in patients with obstructive sleep apnea (OSA). J Clin Sleep Med. 2014 May 15;10(5):465-72. doi: 10.5664/jcsm.3686.
Results publication: PubMed 25232509Quan SF, Budhiraja R, Batool-Anwar S, Gottlieb DJ, Eichling P, Patel S, Shen W, Walsh JK, Kushida CA. Lack of Impact of Mild Obstructive Sleep Apnea on Sleepiness, Mood and Quality of Life. Southwest J Pulm Crit Care. 2014;9(1):44-56. doi: 10.13175/swjpcc082-14.
Results publication: PubMed 24634638Quan SF, Budhiraja R, Clarke DP, Goodwin JL, Gottlieb DJ, Nichols DA, Simon RD, Smith TW, Walsh JK, Kushida CA, Phillips B. You still need more than CPAP for OSA patients to lose weight. J Clin Sleep Med. 2014 Mar 15;10(3):349. doi: 10.5664/jcsm.3552. No abstract available.
Results publication: PubMed 24916094Prilipko O, Huynh N, Thomason ME, Kushida CA, Guilleminault C. An fMRI study of cerebrovascular reactivity and perfusion in obstructive sleep apnea patients before and after CPAP treatment. Sleep Med. 2014 Aug;15(8):892-8. doi: 10.1016/j.sleep.2014.04.004. Epub 2014 May 4.
Results publication: PubMed 24808886Huynh NT, Prilipko O, Kushida CA, Guilleminault C. Volumetric Brain Morphometry Changes in Patients with Obstructive Sleep Apnea Syndrome: Effects of CPAP Treatment and Literature Review. Front Neurol. 2014 Apr 29;5:58. doi: 10.3389/fneur.2014.00058. eCollection 2014.
Individual participant dataSharing planned: Yes. Only in de-identified format to researchers

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

William C. Dement, MD, PhD study chair

Stanford University

Clete A. Kushida, MD, PhD principal investigator

Stanford University

5 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Active CPAP in people with Lung Diseases and Sleep Apnea Syndromes, run by Stanford University at 5 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 2 inclusion and 19 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 28 Nov 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 30 Nov 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Effect of CPAP on Neurocognitive Function: E/F Function- SWMT-OMD (time frame: 2 months and 6 months post intervention). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00051363, which also lists 22 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Nov 2018; AzTrials last refreshed its copy on 28 Oct 2026.