Sleep Apnea Intervention for Cardiovascular Disease Reduction

Study Overview
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Brief Summary
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Moderate to severe sleep apnea (a high number of breathing pauses on a sleep study) is a common health problem that is often associated with loud snoring and sleepiness.The medical term for this problem is obstructive sleep apnea (OSA). People with OSA often have an increased risk for developing heart disease or may already have a diagnosis of heart disease. A clinical research study is being conducted at Brigham and Women's Hospital (BWH) and Beth Israel Deaconess Medical Center (BIDMC) to compare the effects of continuous positive airway pressure (CPAP) to conservative medical therapy with participation in one of four groups: Active-PAP Therapy Group (Active-Beh or Active+Beh): Will receive standard medical treatment for sleep apnea with active-PAP. Participants will be randomized to either: Active-Pap with respiratory therapist visits only Active-Pap with respiratory therapist visits and cognitive behavioral therapist visits. Alternative PAP Group (Sham): Will receive lower air delivery level than active-PAP therapy group. Will also have meetings with respiratory therapist. Conservative Medical Therapy Group (CMT)*: Will receive a free supply of nasal strips for the duration of their treatment period (either 6 months or 12 months) and follow healthy sleep hygiene guidelines for how to change sleep habits to minimize incidences of apneas (breathing disturbances during sleep). Frequent follow-up support with research coordinator. A sleep doctor or cardiologist will have indicated that a potential participant is an appropriate candidate to receive PAP or CMT as acceptable approaches to treat his/her sleep apnea. Participants will be recruited between the ages of 45-75 years who have diagnosed heart disease or between 55-75 years for those who have risk factors for developing heart disease. This is a 6-12 month study** to evaluate alternative ways to address the potential for OSA treatment to reduce heart disease and to identify those features that would strengthen a later, large-scale randomized controlled trial. We will test the hypothesis that active treatment for OSA with CPAP reduces CVD morbidity and mortality. *All randomized participants will be given conservative medical therapy (CMT). **For those randomized after December 31, 2012, follow-up assessment will only be 6 months long

Detailed Description
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In this pilot randomized controlled trial, we will assess the effectiveness of CPAP therapy to reduce the burden of cardiovascular disease (CVD) and CVD risk factors in patients with moderate to severe obstructive sleep apnea (OSA) presenting to a sleep disorders clinic. A total of 700 patients with a new diagnosis of moderate to severe OSA will be recruited from BWH-affiliated sleep disorder clinics, BWH, Massachusetts General Hospital (MGH), and Faulkner Hospital Cardiology Clinics (and similar specialized clinics seeing patients with cardiovascular risk factors, such as endocrinology and hypertensive clinics), Beth Israel Deaconess Medical Center and Joslin Diabetes Center. After completing a 2 week run-in period, randomized participants (approximately 150 participants will be randomized) will undergo baseline and 6 month assessments of key study exposure and outcome variables. Participants will be randomized after completion of Baseline visit. The treatment arms are as follows: The active arms are: Active-PAP treatment delivered using standard respiratory therapist (RT) adherence education and support. (Active-Beh) Active-PAP treatment administered using adherence education and support delivered by a RT and enhanced by a behavioral promotion intervention. (Active+Beh) The control arms are: Conservative Medical Therapy (CMT) Sham-PAP (Sham) Participants randomized before December 31, 2012 (n=108) also will undergo 12 month follow-up assessments. Participants will be offered a 12 month supervised conservative medical therapy (CMT) program for OSA over the duration of the study intervention. Subjects would be contacted at bimonthly intervals by alternating phone and office visits to assess safety, identify adverse events, identify health care utilization, and reinforce protocol adherence. At 6 and 12 months, study outcomes will be reassessed by collecting data from sources. Patients randomized after December 31, 2012 (n=61) will undergo only 6 months of follow-up assessment. Participants will be offered a 6 month supervised conservative medical therapy (CMT) program for OSA over the duration of the study intervention. Subjects would be contacted at bimonthly intervals by alternating phone and office visits to assess safety, identify adverse events, identify health care utilization, and reinforce protocol adherence. At 6 months, study outcomes will be reassessed by collecting data from sources.

Official Title
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A Planning Study: Sleep Apnea Intervention for Cardiovascular Disease Reduction

Conditions
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Obstructive Sleep Apnea

Intervention / Treatment
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* Behavioral: Conservative Medical Therapy (CMT)
* Device: Sham PAP (Sham)
* Device: Active PAP with RT Support (Active-Beh)
* Device: Active PAP with Behavioral Modification (Active+Beh)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Obstructive apnea hypopnea index (AHI) ≥ 15 Age 45-75 years, or 55 to 75 yrs if without established Cardiovascular Disease (CVD) Ability to provide informed consent, with the patient and physician acknowledging accepting uncertainty on the role of PAP in CVD prevention. Established CVD,or having diabetes mellitus, defined by one or more of the following: Prior myocardial infarction Coronary artery revascularization procedure (≥4 months before study entry) Angiographically documented stenosis (>70%) of a major coronary artery Prior ischemic stroke without major functional impairment Diabetes mellitus treated with medication or ≥ 2 fasting glucose levels ≥ 126 mg/dl OR Three or more of the following established CVD risk factors: Hypertension treated with medications or systolic BP > 140 or diastolic BP > 90 on ≥ 2 occasions Male sex BMI ≥ 30 Total cholesterol > 240 mg/dl or LDL cholesterol > 160 mg/dl or HDL < 45 mg/dl > 10 pack years of smoking Exclusion Criteria: Diagnosed heart failure with known cardiac ejection fraction of < 35% or New York Heart Association (NYHA) class 3 or 4 status Less than 4 months since myocardial infarction (MI), stroke or revascularization procedure Poorly controlled hypertension (>170/>100) Prior stroke with functional impairment interfering with ability to complete the protocol Severe uncontrolled medical problems or medications that may influence measurements or impair ability to participate in the study exams (e.g. oral steroids; chronic opioid use; self- reported chronic kidney disease or, if measured, creatinine > 2.5 mg/dl or glomerular filtration rate (GFR) < 30; anemia with Hgb < 10, etc.) Resting oxygen saturation < 90% or nocturnal oxygen saturation <85% for > 10% of the sleep period; Use of prescribed PAP for sleep apnea within the prior 2 years Report of inability to spend >6 hrs in bed Any use of prescribed PAP for sleep apnea Severe sleepiness defined by an Epworth Sleepiness Score of >14 or report of falling asleep driving in the prior 2 years Working as a professional driver Low risk related to having sleep apnea defined by a Berlin Score < 2 Central sleep apnea, with >50% of respiratory events classified as central apneas Refusal to consider PAP use after an initial split-night PAP study (pre-randomization) Concurrent involvement in another research study that will result in a conflict as determined by study doctors

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Conservative Medical Therapy (CMT)<br>All participants will meet with a research assistant who will provide  30 minutes of instruction on sleep hygiene and healthy lifestyle guidelines. Each subject's sleep routine will be reviewed with the aim to identify appropriate bed and wake times that provide a consistent schedule and allow for at least 7 hours of time in bed per night. Habits that may impact sleep, such as alcohol consumption, tobacco use, and exercise close to bedtime will be reviewed with appropriate guidance on how to minimize sleep disrupting exposures. Subjects will be provided external nasal dilator strips (Breath Right®) and advised on how to maximize sleep time in a non-supine position using bed elevation, wedge pillows and/or objects affixed to the back of their night clothes as appropriate. | Behavioral: Conservative Medical Therapy (CMT)<br>* All participants will meet with a research assistant who will provide 30 minutes of instruction on sleep hygiene and healthy lifestyle guidelines. Each subject's sleep routine will be reviewed with the aim to identify appropriate bed and wake times that provide a consistent schedule and allow for at least 7 hours of time in bed per night. Habits that may impact sleep, such as alcohol consumption, tobacco use, and exercise close to bedtime will be reviewed with appropriate guidance on how to minimize sleep disrupting exposures. Subjects will be provided external nasal dilator strips (Breathe Right®) and advised on how to maximize sleep time in a non-supine position using bed elevation, wedge pillows and/or objects affixed to the back of their night clothes as appropriate.<br>* Other names: Breathe Right® external dilator strips;|
| Sham Comparator: Sham PAP (Sham)<br>In addition to receiving CMT, participants in this treatment arm will receive a sham-CPAP unit. Sham devices look like active PAP devices, however, the exhalation port is increased and an orifice-resistor is inserted between the pump and tubing, creating a marginal pressure. A heated humidifier will be provided with this device and PAP masks will be fit and provided following the same procedures as for the active PAP arms. The treatment visit schedule is outlined below. PAP Initial Set-Up 1-week follow up 1-month follow up 3-month follow up 6-month follow up 9-month follow up (will not occur if on a 6-month follow-up protocol) It is estimated that each in-person follow-up adherence visit with the PAP specialist would last  30 minutes. | Behavioral: Conservative Medical Therapy (CMT)<br>* All participants will meet with a research assistant who will provide 30 minutes of instruction on sleep hygiene and healthy lifestyle guidelines. Each subject's sleep routine will be reviewed with the aim to identify appropriate bed and wake times that provide a consistent schedule and allow for at least 7 hours of time in bed per night. Habits that may impact sleep, such as alcohol consumption, tobacco use, and exercise close to bedtime will be reviewed with appropriate guidance on how to minimize sleep disrupting exposures. Subjects will be provided external nasal dilator strips (Breathe Right®) and advised on how to maximize sleep time in a non-supine position using bed elevation, wedge pillows and/or objects affixed to the back of their night clothes as appropriate.<br>* Other names: Breathe Right® external dilator strips;Device: Sham PAP (Sham)<br>* In addition to receiving CMT, participants in this treatment arm will receive a sham PAP unit. Sham devices look like active PAP devices, however, the exhalation port is increased and an orifice-resistor is inserted between the pump and tubing, creating a marginal pressure. A heated humidifier will be provided with this device and PAP masks will be fit and provided following the same procedures as for the active-PAP arms.<br>* Other names: S9 (ResMed);|
| Active Comparator: Active PAP with RT Support (Active-Beh)<br>In addition to receiving CMT, participants will receive active-PAP. The treatment visit schedule is outlined below. PAP Initial Set-Up 1-week follow up (FU) 1-month FU 3-month FU 6-month FU 9-month FU (12-month follow-up protocol only) All visits will take place with a PAP specialist. All follow-up visits will be anchored to the initial PAP set-up visit. At these visits, using the available data from the PAP monitor, the PAP specialist will discuss PAP use, mask leaks, and residual AHI to assist with troubleshooting. Adjustments to equipment would be performed as needed to improve adherence. Each follow-up visit with the PAP specialist will last 30 minutes. | Behavioral: Conservative Medical Therapy (CMT)<br>* All participants will meet with a research assistant who will provide 30 minutes of instruction on sleep hygiene and healthy lifestyle guidelines. Each subject's sleep routine will be reviewed with the aim to identify appropriate bed and wake times that provide a consistent schedule and allow for at least 7 hours of time in bed per night. Habits that may impact sleep, such as alcohol consumption, tobacco use, and exercise close to bedtime will be reviewed with appropriate guidance on how to minimize sleep disrupting exposures. Subjects will be provided external nasal dilator strips (Breathe Right®) and advised on how to maximize sleep time in a non-supine position using bed elevation, wedge pillows and/or objects affixed to the back of their night clothes as appropriate.<br>* Other names: Breathe Right® external dilator strips;Device: Active PAP with RT Support (Active-Beh)<br>* In addition to receiving CMT, participants will receive active-PAP and meet with a PAP-specialist . The CPAP specialist would meet with the participant in person throughout the course of the study (set-up, 1-week, 1-month, 3-month, 6-month, and 9-month). Using the available data from the PAP monitor, the PAP specialist will discuss PAP use, mask leaks, and residual AHI to assist with troubleshooting. Adjustments to equipment would be performed as needed to improve adherence. It is estimated that each in-person follow-up adherence visit with the PAP-specialist would last 30 minutes.<br>* Other names: S9 (ResMed);|
| Active Comparator: Active PAP with Behavioral Modification (Active+Beh)<br>In addition to receiving CMT and active-PAP, participants will have behavioral intervention sessions to promote PAP adherence. The treatment visit schedule is outlined below: Visits with Behavioral Interventionist (in addition to active-PAP treatment visits): PAP Initial Set-Up (in-person, 1-hr) 1-week follow-up (FU) (in-person, 1-hr) 1-month FU 2-month FU 3-month FU 5-month FU 8-month FU (12-month follow-up protocol only) All follow-up visits will be anchored to the initial PAP set-up visit. PAP treatment visits will occur as outlined in the active-PAP arm. All behavioral intervention visits will be 30-min phone calls, unless otherwise noted. The intervention will be based on social cognitive theory and feedback concerning adherence with targeted problem solving training. | Behavioral: Conservative Medical Therapy (CMT)<br>* All participants will meet with a research assistant who will provide 30 minutes of instruction on sleep hygiene and healthy lifestyle guidelines. Each subject's sleep routine will be reviewed with the aim to identify appropriate bed and wake times that provide a consistent schedule and allow for at least 7 hours of time in bed per night. Habits that may impact sleep, such as alcohol consumption, tobacco use, and exercise close to bedtime will be reviewed with appropriate guidance on how to minimize sleep disrupting exposures. Subjects will be provided external nasal dilator strips (Breathe Right®) and advised on how to maximize sleep time in a non-supine position using bed elevation, wedge pillows and/or objects affixed to the back of their night clothes as appropriate.<br>* Other names: Breathe Right® external dilator strips;Device: Active PAP with Behavioral Modification (Active+Beh)<br>* In addition to receiving CMT and active-PAP, participants will meet with a behavioral interventionist in addition to PAP-specialist visits. Participants also would speak with the behavioral interventionist over the course of the study (set up, 1-week, 3-week, 1-month, 2-months, 3-months, 5-months and 8-months). The duration of the first 2 behavioral intervention sessions are estimated to be 1-hour long, with subsequent 30-minutes intervention sessions. The intervention will be based on social cognitive theory and feedback concerning adherence with targeted problem solving training.<br>* Other names: S9 (ResMed);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in 24-hour Blood Pressure at Months 6 and 12 by Pooled Arms | Blood pressure data was collected using a 24-hour ambulatory blood pressure monitor. The 2 Active arms and 2 Control arms were pooled to create a 2-arm analysis. Outcome reported is mean of change from baseline to 6-months and baseline to 12-months. Control arms and Active arms were pooled, respectively, for analysis. | Mean of 6- and 12-months | 
| Difference in CPAP Adherence by Active Treatment Arm | Adherence to CPAP therapy was tracked remotely by modem transmission. Outcome reported is mean hours of PAP use per night at the 6-month timepoint. Comparison is between those with and without assignment to Motivational Enhancement as part of treatment randomization. | 6-months | 
| Change From Baseline in 24-hour Blood Pressure at Months 6 and 12 (4 Arms) | Blood pressure data was collected using a 24-hour ambulatory blood pressure monitor. Average of changes from baseline to 6 months and from baseline to 12 months. | Mean of 6- and 12-months | 
| Change From Baseline in 24-hour Blood Pressure at Month 12 by Pooled Arms | Blood pressure data was collected using a 24-hour ambulatory blood pressure monitor. The 2 Active arms and 2 Control arms were pooled to create a 2-arm analysis. Outcome reported is change from baseline to 12-months. Control arms and Active arms were pooled, respectively, for analysis. | 12-months | 
| Change From Baseline in 24-hour Blood Pressure at Month 6 by Pooled Arms | Blood pressure data was collected using a 24-hour ambulatory blood pressure monitor. The 2 Active arms and 2 Control arms were pooled to create a 2-arm analysis. Outcome reported mean change from baseline to 6-months. Control arms and Active arms were pooled, respectively, for analysis. | 6-months | 
| Change From Baseline in 24-hour Blood Pressure at Month 12 (4 Arms) | Blood pressure data was collected using a 24-hour ambulatory blood pressure monitor. Outcome reported is mean change from baseline to 12-months. | 12-months | 
| Change From Baseline in 24-hour Blood Pressure at Month 6 (4 Arms) | Blood pressure data was collected using a 24-hour ambulatory blood pressure monitor. Outcome reported is mean change from baseline to 6-months. | 6-months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in 36-Item Short Form Survey (SF-36) Measures (4 Arm) | The 36-Item Short Form Survey (SF-36) is a patient-reported survey of patient health. The SF-36 scores range from 0-100, with lower scores indicating greater disability. Outcome reported is mean of change from baseline to 6-months and baseline to 12-months. | Mean of 6- and 12-months | 
| Change in Epworth Sleepiness Scale (ESS) (4 Arm) | The Epworth Sleepiness Scale (ESS) is a scale intended to measure daytime sleepiness. The ESS score ranges from 0 - 24, with higher scores indicating increasing possibility of specific sleep disorders. Outcome reported is mean of change from baseline to 6-months and baseline to 12-months. | Mean of 6- and 12-months | 
| Change in Patient Health Questionnaire (PHQ8) (4 Arm) | The Patient Health Questionnaire (PHQ-8) is a scale intended to measure depression. The PHQ-8 score ranges from 0 24, with higher scores indicating increasing severity of depression. Outcome reported is mean of change from baseline to 6-months and baseline to 12-months. | Mean of 6- and 12-months | 
| Change in the Calgary Sleep Apnea Quality of Life Index (SAQLI) (4 Arm) | The Calgary Sleep Apnea Quality of Life Index (SAQLI) is a scale intended to measure disease-specific quality of life. The SAQLI score ranges from 1 - 7, with higher scores indicating a higher quality of life. Outcome reported is mean of change from baseline to 6-months and baseline to 12-months. | Mean of 6- and 12-months | 
| Change in C-Reactive Protein at Months 6 and 12 (4 Arm) | C-Reactive Protein laboratory measurements were calculated from blood samples collected through fasting phlebotomy. Outcome reported is mean of change from baseline to 6-months and baseline to 12-months. | Mean of 6- and 12-months | 
| Change in Lipid Panel at 6 and 12 Months (4 Arm) | Lipid panel measurements were calculated from blood samples collected through fasting phlebotomy. Outcome reported is mean of change from baseline to 6-months and baseline to 12-months. | Mean of 6- and 12-months | 
| Change in Glucose, Fibrinogen, Creatinine and BNP at Months 6 and 12 (4 Arm) | Glucose, Fibrinogen, Creatinine and BNP measurements were calculated from blood and urine samples collected through fasting phlebotomy and urine collection. Outcome reported is mean of change from baseline to 6-months and baseline to 12-months. | Mean of 6- and 12-months | 
| Change From Baseline in Hemoglobin A1c Percentage at Months 6 and 12 (4 Arm) | Hemoglobin A1c percentage was calculated from blood samples collected through fasting phlebotomy. Outcome reported is mean of change from baseline to 6-months and baseline to 12-months. | Mean of 6- and 12-months | 
| Change From Baseline in Fasting Insulin at Months 6 and 12 (4 Arm) | Fasting Insulin was calculated from blood samples collected through fasting phlebotomy. Outcome reported is mean of change from baseline to 6-months and baseline to 12-months. | Mean of 6- and 12-months | 
| Change in Interleukin 6 (IL-6) at Months 6 and 12 (4 Arm) | Interleukin 6 (IL-6) was calculated from blood samples collected through fasting phlebotomy. Outcome reported is mean of change from baseline to 6-months and baseline to 12-months. | Mean of 6- and 12-months | 
| Change in Glomerular Filtration Rate (GFR) at Months 6 and 12 (4 Arm) | Glomerular Filtration Rate was calculated from blood samples collected through fasting phlebotomy. Outcome reported is mean of change from baseline to 6-months and baseline to 12-months. | Mean of 6- and 12-months | 
| Change in Urine Microalbumin at Months 6 and 12 (4 Arm) | Urine Microalbumin was calculated from urine samples. Outcome reported is mean of change from baseline to 6-months and baseline to 12-months. | Mean of 6- and 12-months | 
| Change in Urinary Albumin Creatinine Ratio at Months 6 and 12 (4 Arm) | Urinary Albumin Creatinine Ratio was calculated from urine samples. Outcome reported is mean of change from baseline to 6-months and baseline to 12-months. | Mean of 6- and 12-months | 
| Change in Plasminogen Activator Inhibitor-1 (PAI-1) at Months 6 and 12 (4 Arm) | Plasminogen Activator Inhibitor-1 (PAI-1) was calculated from blood samples. Outcome reported is mean of change from baseline to 6-months and baseline to 12-months. | Mean of 6- and 12-months | 
| Change in Pulse Wave Velocity (PWV) at Months 6 and 12 (4 Arms) | Tonometry measurements of arterial stiffness were collected using a Sphygmacor. Outcome reported is mean of change from baseline to 6-months and baseline to 12-months. | Mean of 6- and 12-months | 
| Change in Augmentation Index at Months 6 and 12 (4 Arms) | Tonometry measurements of arterial stiffness were collected using a Sphygmacor. Outcome reported is mean of change from baseline to 6-months and baseline to 12-months. | Mean of 6- and 12-months | 
| Left Ventricular (LV) Mass Index (4 Arm) - Baseline | Baseline Left Ventricular Mass Index measured via echocardiography. | 12-months | 
| Left Atrial (LA) Volume Index (4 Arm) - Baseline | Baseline Left Atrial Mass Index measured via echocardiography. | 12-months | 
| End-Diastolic Volume (4 Arm) - Baseline | Baseline End-Diastolic Volume measured via echocardiography. | 12-months | 
| Ejection Fraction (4 Arm) - Baseline | Baseline Ejection Fraction measured via echocardiography. | 12-months | 
| Right Ventricular Fractional Area Change (4 Arm) - Baseline | Baseline RV Fractional Area Change measured via echocardiography. | 12-months | 
| Tricuspid Annular Peak Systolic Myocardial Velocity (4 Arm) - Baseline | Baseline Tricuspid Annular Peak Systolic Myocardial Velocity measured via echocardiography. | 12-months | 
| Pulmonary Vascular Resistance (4 Arm) - Baseline | Baseline Pulmonary Vascular Resistance measured via echocardiography. | 12-months | 
| E/Em Lateral Ratio (4 Arm) - Baseline | Baseline E/Em Lateral Ratio measured via echocardiography. | 12-months | 
| Peak Tricuspid Regurgitation Velocity (4 Arm) - Baseline | Baseline Peak Tricuspid Regurgitation Velocity measured via echocardiography. | 12-months | 
| Left Ventricular Mass Index (4 Arm) - 12 Month | Endpoint Left Ventricular Mass Index measured via echocardiography. | 12-months | 
| Left Atrial Volume Index (4 Arm) - 12 Month | Endpoint Left Atrial Volume Index measured via echocardiography. | 12-months | 
| End-Diastolic Volume (4 Arm) - 12 Month | Endpoint End-Diastolic Volume measured via echocardiography. | 12-months | 
| Ejection Fraction (4 Arm) - 12 Month | Endpoint Ejection Fraction measured via echocardiography. | 12-months | 
| Right Ventricular Fractional Area Change (4 Arm) - 12 Month | Endpoint Right Ventricular Fractional Area Change measured via echocardiography. | 12-months | 
| Tricuspid Annular Peak Systolic Myocardial Velocity (4 Arm) - 12 Month | Endpoint Tricuspid Annular Peak Systolic Myocardial Velocity measured via echocardiography. | 12-months | 
| Pulmonary Vascular Resistance (4 Arm) - 12 Month | Endpoint Pulmonary Vascular Resistance measured via echocardiography. | 12-months | 
| E/Em Lateral Ratio (4 Arm) - 12 Month | Endpoint E/Em Lateral Ratio measured via echocardiography. | 12-months | 
| Peak Tricuspid Regurgitation Velocity (4 Arm) - 12 Month | 12 Month Peak Tricuspid Regurgitation Velocity measured via echocardiography. | 12-months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sleep Apnea, Heart Disease, Risk factors for heart disease