Apnea Positive Pressure Long-Term Efficacy Study

Sleep Clinical Trial

— APPLES  

Official title:

APPLES: Apnea Positive Pressure Long-Term Efficacy Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00051363
• Other study ID #: 150
• Secondary ID: U01HL068060
• Status: Completed
• Phase: Phase 3
• Start date: September 2002
• Est. completion date: September 2008

Study information

• Verified date: November 2018
• Source: Stanford University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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).

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1105
• Est. completion date: September 2008
• Est. primary completion date: August 2008
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Apnea
• Lung Diseases
• Sleep
• Sleep Apnea Syndromes

Intervention

Device:
• Active CPAP
Nightly nasal continuous positive airway pressure (CPAP)
• Sham CPAP
Sham CPAP machine will be used for participants in the placebo group.

Locations

Country	Name	City	State
United States	Brigham & Women's Hospital	Boston	Massachusetts
United States	St. Luke's Hospital	Chesterfield	Missouri
United States	Stanford University School of Medicine	Palo Alto	California
United States	University of Arizona AHSC	Tucson	Arizona
United States	St. Mary Medical Center	Walla Walla	Washington

Sponsors (2)

Lead Sponsor	Collaborator
Stanford University	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

References & Publications (16)

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. — View Citation

Batool-Anwar S, Goodwin JL, Kushida CA, Walsh JA, Simon RD, Nichols DA, Quan SF. Impact of continuous positive airway pressure (CPAP) on quality of life in patients with obstructive sleep apnea (OSA). J Sleep Res. 2016 Dec;25(6):731-738. doi: 10.1111/jsr. — View Citation

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 — View Citation

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. — View Citation

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. — View Citation

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. eCol — View Citation

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 — View Citation

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. — View Citation

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 Ma — View Citation

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/journ — View Citation

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 — View Citation

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. — View Citation

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. — View Citation

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):9 — View Citation

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 neurocogniti — View Citation

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. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

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