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Apnea Positive Pressure Long-Term Efficacy Study (APPLES)

This study has been completed.
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Clete A. Kushida, Stanford University
ClinicalTrials.gov Identifier:
NCT00051363
First received: January 9, 2003
Last updated: October 6, 2016
Last verified: October 2016
  Purpose
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).

Condition Intervention Phase
Lung Diseases
Sleep Apnea Syndromes
Sleep
Device: Active CPAP
Device: Sham CPAP
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: APPLES: Apnea Positive Pressure Long-Term Efficacy Study

Resource links provided by NLM:


Further study details as provided by Stanford University:

Primary Outcome Measures:
  • Effect of CPAP on Neurocognitive Function: E/F Function- SWMT-OMD [ Time Frame: 2 months and 6 months post intervention ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]

    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 ] [ Designated as safety issue: No ]

    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)



Secondary Outcome Measures:
  • Attention and Psychomotor (A/P) Function: Pathfinder Number- Reaction Time (PN-RT) [ Time Frame: 2 months and 6 months post intervention ] [ Designated as safety issue: No ]

    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)


  • Attention and Psychomotor (A/P) Function: Psychomotor Vigilance Task- Median Reaction Time (PVT-MedRT) [ Time Frame: 2 months and 6 months post intervention ] [ Designated as safety issue: No ]

    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)


  • 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 ] [ Designated as safety issue: No ]

    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)


  • 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 ] [ Designated as safety issue: No ]
    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).

  • 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 ] [ Designated as safety issue: No ]

    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.


  • Executive and Frontal-Lobe (E/F) Function: SWMT- Mid-day Activation Index (SWMT-ActMD) [ Time Frame: 2 months and 6 months post intervention ] [ Designated as safety issue: No ]

    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.


  • 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 ] [ Designated as safety issue: No ]

    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)


  • 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 ] [ Designated as safety issue: No ]

    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.


  • 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 ] [ Designated as safety issue: No ]

    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.


  • Mood [ Time Frame: Measured at diagnostic visit (baseline) and 2 months and 6 months post intervention ] [ Designated as safety issue: No ]
  • Quality of Life: Calgary Sleep Apnea Quality of Life Index- Total Score (SAQLI-TS) [ Time Frame: diagnostic visit (baseline) ] [ Designated as safety issue: No ]
    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.


Other Outcome Measures:
  • Functional Magnetic Resonance Imaging (fMRI) [ Time Frame: Measured at diagnostic visit (baseline) and 6 months post intervention ] [ Designated as safety issue: No ]

Enrollment: 1105
Study Start Date: September 2002
Study Completion Date: September 2008
Primary Completion Date: August 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Active CPAP
Active Continuous Positive Airway Pressure (CPAP)
Device: Active CPAP
Nightly nasal continuous positive airway pressure (CPAP)
Other Name: Positive Pressure Respiration
Placebo Comparator: Sham CPAP
Sham Continuous Positive Airway Pressure (CPAP)
Device: Sham CPAP
Sham CPAP machine will be used for participants in the placebo group.
Other Name: Sham CPAP machine

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).

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female adults age 18 years or older with a diagnosis of OSAS using clinical criteria defined by the study protocol
  • Study participation may require seven or more laboratory visits over six months

Exclusion Criteria:

  • Prior treatment for OSAS with continuous positive airway pressure or surgery
  • Potential sleep apnea complications that may affect the health or safety of the participant, including low blood oxygen, recent near-miss or prior automobile accident due to sleepiness, congestive heart failure, history of angina, coronary artery disease, myocardial infarction or stroke, cardiac rhythm disturbance, and chronic neurological disorders affecting neurocognitive abilities or daily function
  • The use of hypnotics, anxiolytics, sedating antidepressants, anticonvulsants, sedating antihistamines, stimulants or other medications likely to affect neurocognitive function and/or alertness
  • Respiratory disease requiring medications (unless on stable medications for 2 months)
  • Cancer, unless in remission for greater than one year and not taking exclusionary medications
  • Self-reported renal failure
  • Pregnancy anytime during a subject's participation
  • Psychiatric illness, as defined by a DSM-IV diagnosis, except for depression or mild anxiety
  • Narcolepsy, idiopathic hypersomnolence, DSM-IV chronic insomnia, restless legs syndrome, or rapid eye movement (REM) behavior disorder
  • Current use of diurnal or nocturnal supplemental oxygen
  • Significant vision, hearing, or coordination problems
  • Difficulty understanding or speaking English
  • Currently working night or rotating shifts
  • Consumption of more than 10 caffeinated beverages per day (approximately 1,000 mg per day)
  • Smokers whose habit interferes with the overnight polysomnogram or with the battery of testing during the day
  • Consumption of more than 2 alcoholic beverages per day
  • Any illicit drug usage or marijuana usage more than once a week
  • Any individual in the household currently on CPAP or on CPAP in the past
  • A score of 26 or less on the Mini Mental State Examination (MMSE)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00051363

Locations
United States, Arizona
University of Arizona AHSC
Tucson, Arizona, United States, 85724
United States, California
Stanford University School of Medicine
Palo Alto, California, United States, 94305
United States, Massachusetts
Brigham & Women's Hospital
Boston, Massachusetts, United States, 02459
United States, Missouri
St. Luke's Hospital
Chesterfield, Missouri, United States, 63017
United States, Washington
St. Mary Medical Center
Walla Walla, Washington, United States, 99362
Sponsors and Collaborators
Stanford University
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
Study Chair: William C. Dement, MD, PhD Stanford University
Principal Investigator: Clete A. Kushida, MD, PhD Stanford University
  More Information

Publications:

Responsible Party: Clete A. Kushida, Principal Investigator, Stanford University
ClinicalTrials.gov Identifier: NCT00051363     History of Changes
Other Study ID Numbers: 150  U01HL068060 
Study First Received: January 9, 2003
Results First Received: February 29, 2016
Last Updated: October 6, 2016
Health Authority: United States: Federal Government
Individual Participant Data  
Plan to Share IPD: Yes
Plan Description: Only in de-identified format to researchers

Keywords provided by Stanford University:
Obstructive Sleep Apnea

Additional relevant MeSH terms:
Apnea
Sleep Apnea Syndromes
Lung Diseases
Respiration Disorders
Respiratory Tract Diseases
Signs and Symptoms, Respiratory
Signs and Symptoms
Sleep Disorders, Intrinsic
Dyssomnias
Sleep Wake Disorders
Nervous System Diseases

ClinicalTrials.gov processed this record on December 08, 2016