Vascular Impairment in Type II Diabetes Mellitus With Co-morbid Obstructive Sleep Apnea.
Phase: PHASE2
Conditions: Sleep Apnea, Obstructive, Diabetes Mellitus
Sponsor: Sanjay R Patel

Official Title: Vascular Impairment in Type II Diabetes Mellitus with Co-Morbid Obstructive Sleep Apnea 
ClinicalTrials.gov ID (NCT number): NCT01629862 
Protocol Date: 4/28/2017 

PARTNERS HUMAN RESEARCH COMMITTEE 
PROTOCOL SUMMARY 
Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
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Answer all questions accurately and completely in order to provide the PHRC with the relevant 
information to assess the risk-benefit ratio for the study.  Do not leave sections blank. 
 
PRINCIPAL/OVERALL INVESTIGATOR 
 
Jessie Bakker, PhD 
 
PROTOCOL TITLE 
 
Vascular impairment in type II diabetes mellitus with co-morbid obstructive 
sleep apnea 
 
FUNDING 
 
National Institutes of Health (NIH) R01-HL110350; American Heart 
Association (AHA) 14SDG20160000. 
 
VERSION DATE 
 
Version 27; 28 April 2017 
 
SPECIFIC AIMS 
Concisely state the objectives of the study and the hypothesis being tested. 
 
Although both diabetes mellitus (DM) and obstructive sleep apnea (OSA) 
have adverse effects on endothelial function, it is not clear whether these 
two conditions diverge regarding their action on the vascular smooth muscle 
cell and various inflammatory pathways.  We will investigate the interaction 
between diabetes mellitus (DM) and obstructive sleep apnea (OSA) on 
vascular functioning by performing a two-part study. 
 
Aim 1: To compare the vascular physiology of matched controls, patients 
with DM alone, patients with OSA alone, and patients with DM+OSA.  We 
hypothesize that OSA and DM will demonstrate a synergistic effect on 
cardiovascular risk, demonstrated by patients with DM+OSA displaying 
impaired vascular reactivity compared with patients with DM or OSA alone. 
 
Aim 2: In a 3-month, double blinded randomized controlled trial, to compare 
the vascular physiology of patients with both DM and OSA, receiving either 
active continuous positive airway pressure (CPAP) or sham-CPAP.  We 
hypothesize that patients treated with active CPAP will show significant 
improvements in vascular reactivity compared with those assigned sham-
CPAP. 
 

Partners Human Subjects Research Application Form 
 
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
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BACKGROUND AND SIGNIFICANCE 
Provide a brief paragraph summarizing prior experience important for understanding the 
proposed study and procedures. 
 
The obesity pandemic has led to the increased prevalence of major 
complications including DM and OSA.  Various studies have shown important 
improvements in the vascular complications of DM, however refinements in 
glycemic control have not always led to improvements in the macrovascular 
complications of DM.  Thus, some have suggested that alternative 
therapeutic pathways need to be targeted to lower vascular complication 
rates further. 
 
One such potential target is OSA.  OSA is highly prevalent (up to 86%) in 
obese people with DM, and yet only a fraction of these patients are currently 
being diagnosed, and even fewer are currently receiving therapy for OSA.  
OSA has been established as a significant cardiovascular risk factor 
independent from co-morbidities including DM.  However, there is a 
possibility that there may be interactions between DM and OSA, such that 
vascular risk may be increased by both conditions, or that the overall risk 
may be limited by ceiling effects of the two diseases.  
 
Previous research conducted by the PI and co-investigators has established 
that OSA subjects have impaired macrovascular functioning compared to 
both lean and obese controls, but similar to lean and obese patients with 
DM.  In contrast, microvascular functioning in the OSA subjects was shown 
to be similar to the lean and obese controls and higher than the lean and 
obese DM patients.  Various inflammatory cytokines were also shown to be 
expressed to a greater degree in OSA patients compared with both controls 
and DM patients.  Hence, although both OSA and DM affect endothelial 
function, the conditions may diverge regarding their action on the vascular 
smooth muscle cell and inflammatory pathways. 
 
RESEARCH DESIGN AND METHODS 
Briefly describe study design and anticipated enrollment, i.e., number of subjects to be enrolled 
by researchers study-wide and by Partners researchers.  Provide a brief summary of the 
eligibility criteria (for example, age range, gender, medical condition).  Include any local site 
restrictions, for example, “Enrollment at Partners will be limited to adults although the sponsor’s 
protocol is open to both children and adults.”
 
As mentioned under ‘Specific Aims’ above, the study consists of a cross-
sectional study followed by a 3-month, double-blinded randomized controlled 
trial.  All subjects will be enrolled by Partners researchers; there are 
therefore no local site restrictions.   
 

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Version Date:  June 1, 2005 
 
  
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For Aim 1 (cross-sectional study), we plan to enroll four groups of 40 
subjects each: healthy controls, patients with OSA alone, patients with DM 
alone, and patients with DM+OSA.  All four groups will be matched for age, 
gender, and body mass index (BMI), as well as duration of DM where 
appropriate.  
 
For Aim 2 (randomized controlled trial), we plan to enroll 55 patients with 
DM+OSA.  Data for all of these patients will be included in Aim 1, with 
additional data to be collected for Aim 2. 
 
Inclusion Criteria 
 
All patients: ≤70 years of age, weight ≤450 pounds (the maximum 
supported by the cardiac magnetic resonance (CMR) imaging table). 
OSA patients: Respiratory disturbance index (RDI) ≥10 and <100 
events/hour determined during two consecutive home sleep studies; no 
evidence of non-OSA sleep disorders, Epworth Sleepiness Scale (ESS) score 
≤18 (/24) indicating normal/moderate daytime sleepiness levels, no history 
of motor vehicle accident/s or near-miss accident/s related to sleepiness 
within the previous two years; not a commercial driver; naïve to CPAP 
treatment; not currently receiving treatment of any kind for OSA. 
 
DM patients: A clinical diagnosis of type 2 DM; glycated hemoglobin (HbA1c) 
<8.0% indicating stable glycemic control. 
 
Healthy controls: Normal fasting plasma glucose (<100 mg/dl); RDI<10 
events/hour determined during two consecutive home sleep studies; no 
evidence of any other sleep disorder/s. 
 
Exclusion Criteria 
 
All patients: Hematocrit <32, metallic implants or other contraindication of 
CMR; pregnancy; collagen vascular disease; hepatic or renal disease; 
cardiopulmonary disease; use of 
medications that could affect 
sleep/breathing, or that could interact with nitroglycerin, non-English 
speakers. 
 
Briefly describe study procedures.  Include any local site restrictions, for example, “Subjects 
enrolled at Partners will not participate in the pharmacokinetic portion of the study.”  Describe 
study endpoints.
 
The study procedure for Aim 1 (visits 1-2) will be the same for all four 
subject groups (healthy controls, OSA patients, DM patients, OSA+DM 
patients).  Patients enrolling in Aim 2 will first complete Aim 1 (visits 1-2) 
followed by Aim 2 (visits 3-6).   
 

Partners Human Subjects Research Application Form 
 
 
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Version Date:  June 1, 2005 
 
  
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Study procedures will take place at different locations within Longwood 
Medical Area.  In the case of inclement weather or if the subject does not 
wish to walk, a taxi or shuttle bus will be arranged to transport subjects.  
Subjects will be accompanied between sites at all times until the final 
procedure of each visit, apart from times when the subject will be in a 
hospital/clinic waiting room. 
 
• Visit 1: Screening Visit 
 
Location: BWH Ambulatory Clinical Center or BWH Clinical Trial Center 
Time Required: Approximately 2.0 hours 
Staff Responsible: Licensed physician, co-investigator, ACC/CTC nursing 
staff 
 
All subjects will attend the BWH ACC or BWH CTC for a screening visit.  Only 
patients who have indicated that they do not take medication/s for type 2 
diabetes will be required to attend fasting.  Eligibility criteria will be re-
assessed verbally, and informed consent sought by a co-investigator who is 
not directly involved in the subject’s clinical care.  A licensed physician will 
conduct a physical examination (blood pressure, height and weight, neck, 
waist and hip circumference), and a thorough endocrine examination.  The 
battery of questionnaires will then be completed.  A urine sample will be 
obtained from females of menstrual age so that a pregnancy test can be 
performed; a positive result is grounds for exclusion from the study.  A 
screening blood sample of approximately 30mL will be taken by the 
ACC/CTC nursing staff in order to assess exclusion criteria (plasma glucose, 
glycated hemoglobin, hematocrit, and eGFR).  All subjects will be shown how 
to fill in the sleep diary, which they will complete during the seven days 
immediately preceding the two home sleep studies.  Subjects will be given a 
list of foods containing a high amount of nitrates, and requested to avoid 
these foods during the three days immediately preceding visit 2 (and visit 6, 
if completing the randomized controlled trial).   
 
Lastly, all subjects will be given a home sleep study device and shown how 
to operate it.  They will take this home, and when final results of screening 
blood samples are available, a co-investigator will contact them via 
telephone.  Those meeting entry criteria for the study will be asked to begin 
the 1-week sleep diary followed by two consecutive home-based sleep 
studies.  Visit 2 will be scheduled, and subjects will bring the sleep study 
device to this appointment.  Those who do not meet entry criteria will be 
asked to return the device to the investigators (at investigators’ expense). 
 
List of questionnaires: 
• Clinical Sleep Questionnaire including Epworth Sleepiness Scale; 
• Short-Form 36 Health Survey; 
• Pittsburgh Sleep Quality Index; 

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• Functional Outcomes of Sleep Questionnaire; 
• Rapid Eating Assessment for Patients; 
• Typical Week Physical Activity Survey; 
• BIDMC Cardiac MR Center Questionnaire. 
 
• Visit 2: Vascular Testing, Cardiac MRI and Exercise Study 
 
Locations: BWH Ambulatory Clinical Center or BWH Clinical Trial Center 
(early morning), BIDMC Microcirculation Laboratory (mid-morning), BIDMC 
MRI Laboratory (late morning), BWH Shapiro Cardiovascular Center (early 
afternoon) 
Time Required: Approximately 5 hours 
Staff Responsible: Licensed physician, ACC/CTC nursing staff, MRI 
technician, co-investigator 
 
Subjects will arrive at the ACC/CTC in the morning, in a fasting state.  
Fasting will continue until the completion of vascular testing.  DM subjects 
will not take their short-acting insulin and/or oral hypoglycemic agents 
during the fasting. 
 
Data will be downloaded from the home sleep study device using custom 
software.  The respiratory disturbance index (RDI) will be calculated; 
subjects with a RDI<10 will continue the study in either the DM only group 
or the healthy control group, and subjects with a RDI≥10 will continue the 
study in either the OSA only group or the DM+OSA group.   
 
A blood sample (approximately 90mL) will be obtained by the ACC/CTC staff.  
3-lead ECG will be recorded for ten minutes while seated.  A non-invasive 
pulse wave analysis reading will be taken, which uses a small sensor placed 
on the wrist. 
 
A co-investigator will accompany each subject to the BIDMC Microcirculation 
Laboratory where vascular testing will take place.  Macrocirculation testing 
involves taking an ultrasound video of the brachial artery before and after a 
cuff is placed on the upper arm at supra-systolic pressure for five minutes, 
and before and after the administration of nitroglycerin.  Microcirculation 
testing involves monitoring the blood flow of the forearm before and after 
the administration of acetylcholine and sodium nitroprusside.  A licensed 
physician will then take two skin punch biopsies (used to evaluate potential 
changes in cellular proteins such as eNOS, P-eNOS, A20 or TNF-alpha, which 
may be up- or down-regulated with OSA and/or DM).  Finally, DM patients 
will undergo a brief neuropathy evaluation. 
 
All subjects will be provided with lunch, then accompanied to the BIDMC MRI 
Laboratory for a cardiac MRI scan.   
 

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Following the MRI, subjects will be accompanied to the BWH Shapiro 
Cardiovascular Center for optional exercise testing. Subjects will be asked to 
cycle for up to 30 minutes on an exercise machine until peak exercise, as 
determined by the patient, is reached. Heart rate and blood pressure will be 
monitored throughout.  The exercise testing will add approximately 1 hour to 
Visit 2, when applicable. 
   
 
Subjects enrolled in Aim 1 only (i.e. healthy controls, those with DM 
only, and those with OSA only), will finish the study at this point.  The 
following visits are for subjects with DM+OSA who have consented to 
the 3-month randomized controlled trial. 
 
• Visit 3: Beginning of Run-In Phase 
 
Location: BWH Ambulatory Clinical Center or BWH Clinical Trial Center 
Time Required: Approximately 30 minutes 
Staff Responsible: Co-investigator 
 
Subjects will be fitted with a mask and shown how to wear and clean it 
appropriately.  If the subject finds the mask comfortable during this time, 
they will take it home and attempt to wear it while awake and/or asleep at 
home. 
 
• Visit 4: Randomization & Device Allocation 
 
Location: BWH Ambulatory Clinical Center or BWH Clinical Trial Center 
Time Required: Approximately 1 hour 
Staff Responsible: Co-investigator 
 
Subjects who did not tolerate wearing the mask during the run-in phase will 
be excluded at this point. 
 
Eligible subjects will be randomized to the treatment arm (active CPAP) or 
placebo arm (sham CPAP) of the trial.  All subjects will be given a device 
which can be set to sham CPAP, active CPAP, or auto-PAP.  The devices are 
identical, and subjects will not be aware of the settings in their allocated 
device. 
 
Those assigned to the active CPAP group will need to undergo a one-week 
titration procedure using auto-PAP in order to determine a therapeutic 
pressure for ongoing CPAP use; the device will be set to auto-PAP mode.  
Those assigned to the sham CPAP group will not need to undergo a titration; 
the device will be set to sham CPAP mode. 
 

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Version Date:  June 1, 2005 
 
  
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Time will be available for questions and troubleshooting, with emphasis 
placed on strategies to maximize adherence. 
 
• Visit 5: Beginning of Randomized Controlled Trial 
 
Location: BWH Ambulatory Clinical Center or BWH Clinical Trial Center 
Time Required: Approximately 30 minutes 
Staff Responsible: Co-investigator 
 
All subjects will return after one week, when adherence data will be 
downloaded from each device.   
 
Subjects who are to continue with sham CPAP will have their device returned 
to them with no changes, although they will not be aware as to whether the 
mode of treatment has been changed.  Subjects assigned to the active 
treatment group will also have pressure information downloaded from their 
device.  A co-investigator will analyze these data and decide on a suitable 
fixed CPAP pressure.  The mode of the device will be changed to active CPAP 
at this pressure, but again, the subjects will not know whether the settings 
of the device have been changed. 
 
Time will be available for questions and troubleshooting, with emphasis 
placed on strategies to maximize adherence. 
 
Subjects will use their sham / active CPAP devices for the next three months 
at home.  During this time, subjects will attend face-to-face meetings with 
an unblinded co-investigator as required and/or requested by the subject.  
Subjects will perform regular blood sugar checks as needed.  It may be 
necessary for some subjects to undergo an additional home-based sleep 
study while using active or sham CPAP; advice will be sought by a licensed 
physician. 
 
• Visit 6: End-Trial Vascular Testing & Cardiac MRI 
 
Locations: BWH Ambulatory Clinical Center or BWH Clinical Trial Center 
(early morning), BIDMC Microcirculation Laboratory (mid-morning), BIDMC 
MRI Laboratory (late morning), BWH Shapiro Cardiovascular Center (early 
afternoon) 
Time Required: Approximately 5 hours 
Staff Responsible: Licensed physician, ACC/CTC nursing staff, MRI 
technician, co-investigator 
 
After three months of sham/active CPAP, subjects will return to the ACC or 
CTC in a fasting state.  Adherence data will be downloaded from each 
device, followed by a repeat ECG measurement, questionnaires, pulse wave 
analysis, pregnancy testing and blood samples (approximately 90mL). 

Partners Human Subjects Research Application Form 
 
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
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A co-investigator will accompany the subject to the BIDMC Microcirculation 
Laboratory for repeat vascular testing, skin biopsies, and a neuropathy 
evaluation. 
 
All subjects will be provided with lunch, then accompanied to the BIDMC MRI 
Laboratory for a repeat cardiac MRI scan.  
 
• Post-Enrollment: CPAP Follow-Up 
 
Following Visit 6, a research assistant will access the medical record of each 
patient (either Beth Israel Deaconess Medical Center, or Brigham and 
Women’s Hospital) to collect data regarding current CPAP use.  If no data 
are found in the medical record, a research assistant will call each patient to 
gather this information over the phone. 
 
The purpose of this follow-up is to investigate long-term engagement with 
sleep therapy following enrollment in a clinical trial.  All patients who were 
recruited from sleep clinics were offered an appointment with their sleep 
specialist after study completion for ongoing sleep care. All patients who 
were recruited from other sources were offered a referral to a local sleep 
physician.  We are interested in determining the rates of attendance at these 
clinical visits, and ascertaining whether there are differences in long-term 
CPAP usage by recruitment source. 
 
 
For studies involving treatment or diagnosis, provide information about standard of care at 
Partners (e.g., BWH, MGH) and indicate how the study procedures differ from standard care.  
Provide information on available alternative treatments, procedures, or methods of diagnosis.
 
Patients with DM will already have a clinical diagnosis and will be well-
established on treatment.  We therefore do not suspect that we will identify 
any patients with undiagnosed DM.  However, if this occurs, the primary 
care physician will be informed of the diagnosis with permission from the 
patient.   
 
Patients with a high likelihood of having OSA in the clinical setting would 
have a diagnostic sleep study performed (either at home or in the 
laboratory).  A CPAP titration would then occur if OSA is demonstrated (with 
the titration either performed manually overnight, or using an auto-PAP 
device at home).  Patients in Aims 1 and 2 of the research study will all 
undergo two consecutive home sleep studies, and many will be diagnosed 
with OSA at that point.  Patients with a diagnosis of OSA who are either not 
eligible for Aim 2, or do not wish to participate in Aim 2, will discuss their 
diagnosis with Dr. Bakker who will advise the patient as to the best way of 

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obtaining treatment.  The diagnostic report will be forwarded to the primary 
care physician with permission of the patient. 
 
Patients who continue to Aim 2 will be randomized to either active-CPAP or 
sham-CPAP.  Patients who are well-established on active CPAP during the 
trial will continue their treatment once the study has finished, with the cost 
of their CPAP equipment to be met by their insurance provider.  Patients in 
this group who do not tolerate active-CPAP will be referred to a sleep 
physician so that alternative treatments (such as oral devices, or surgery) 
can be arranged.  The cost of this will be met by the patient and/or their 
insurance provider.  Patients randomized to the sham CPAP arm will require 
a titration on active CPAP at the conclusion of the study.  A referral will be 
organized for these patients.  The cost of the titration and equipment will be 
met by the patient and/or their insurance provider. 
 
Describe how risks to subjects are minimized, for example, by using procedures which are 
consistent with sound research design and which do not unnecessarily expose subjects to risk or 
by using procedures already being performed on the subject for diagnostic or treatment purposes.
 
Most of the techniques described in this protocol are associated with minimal 
discomfort.  Blood draws and skin biopsies will be conducted under sterile 
conditions by experienced nursing staff, and a licensed physician 
respectively. 
 
Overnight 
sleep 
studies, 
BP 
measurements, 
ECG 
measurements, pulse wave analysis and all vascular testing procedures and 
CMR imaging are generally well-tolerated, and are carried out by trained 
staff members.  All procedures outlined in this protocol have been used by 
the PI and co-investigators in previous studies without incident. 
 
Describe explicitly the methods for ensuring the safety of subjects.  Provide objective criteria for 
removing a subject from the study, for example, objective criteria for worsening disease/lack of 
improvement and/or unacceptable adverse events.  The inclusion of objective drop criteria is 
especially important in studies designed with placebo control groups.
 
Subjects will not be entered into the study unless they are healthy, other 
than having DM and/or OSA.  All procedures (blood drawing, skin biopsies, 
vascular testing, CMR imaging, exercise testing) are conducted by trained 
staff members, who will monitor patients at all times. 
 
Skin biopsies will be performed by a licensed physician under sterile 
conditions.  Lidocaine is injected intradermally to provide adequate 
anesthesia.  After the skin biopsy is taken, adequate pressure will be applied 
to the wound until satisfactory hemostasis has been obtained.  Steri-strips 
will be applied afterwards, and careful instructions on how to care for the 
wound and avoid infection will be provided.  All subjects are given a licensed 

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physician’s phone number and pager to reach 24 hours a day in case of 
emergency.  
 
If any pain or discomfort is noted by the subject during inflation of the blood 
pressure cuff during FMD, testing will be aborted.  Nitroglycerin is given to 
the subjects during NID by a licensed physician. Subjects will be monitored 
for a minimum of ten minutes after administration of nitroglycerin.  A 
licensed physician is required to confirm that the subject has not 
experienced an adverse event related to nitroglycerin, before the subject 
leaves the premises. 
 
Subjects agreeing to CMR imaging will be excluded if they have any MRI 
contraindications such as metallic implants (e.g. pacemaker). These studies 
will be performed in MRI suites that are properly staffed and equipped for 
clinical patient scanning at BWH.  Subjects will be given earplugs to 
minimize noise that occurs during imaging.  The operator and subject will 
communicate with each other while the images are captured to ensure the 
subject’s comfort.  CMR imaging for LV function and structure is non-
invasive and does not use ionizing radiation. Before discharge, it will be 
stressed that all subjects will have the opportunity for restorative sleep in 
the hospital if they intend driving home.  Taxi vouchers will be provided if 
necessary. 
 
Researchers will be in regular contact with subjects over the 3-month sham / 
CPAP treatment period.  Any subject in the sham-CPAP arm who experiences 
a sleepiness-related accident or near-miss during this time will be removed 
from the study.  However, given that patients experiencing excessive 
daytime sleepiness at baseline will not meet study entry criteria, this is 
unlikely to occur.  
 
Subjects will be accompanied between sites at all times until the final 
procedure of each visit, apart from times when the subject will be in a 
hospital/clinic waiting room. 
 
All adverse events possibly related to study interventions will be reviewed in 
weekly meetings, and serious adverse events related to the study 
procedures will be promptly reported to Partners Human Research 
Committee (PHRC) and the hospital authorities.  Guidelines of the PHRC 
regarding reporting of adverse events will be followed.  The study will be 
stopped if any unexpected serious adverse events are found possibly related 
to study interventions that threaten general health and well-being of study 
subjects. 
 
FORESEEABLE RISKS AND DISCOMFORTS 
Provide a brief description of any foreseeable risks and discomforts to subjects.  Include those 
related to drugs/devices/procedures being studied and/or administered/performed solely for 

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research purposes.  In addition, include psychosocial risks, and risks related to privacy and 
confidentiality.  When applicable, describe risks to a developing fetus or nursing infant.
 
Blood pressure measurements are generally well-tolerated, although the 
cuffs can occasionally cause some discomfort.  ECG monitoring is not painful, 
though the sensors can cause some skin irritation.  Pulse wave analysis is 
generally well-tolerated, as the sensor is placed on the wrist and is therefore 
non-invasive.  Blood drawing can cause some initial pain and minor bruising, 
with minor risk of infection and a theoretical possibility of anemia.  Sleep 
studies can lead to poor sleep quality and therefore sleepiness the following 
day.  Measurement of brachial artery flow-mediated dilation can be 
uncomfortable due to the ischemic stimulus to the upper arm, but this 
discomfort rarely requires the procedure to be stopped.  Measurement of 
nitroglycerin-induced dilation can lead to headaches in some cases.  
Monitoring of skin blood flow with laser Doppler can occasionally cause 
redness to the heated area which disappears soon after the measurement is 
complete.  Iontophoresis of acetylcholine / sodium nitroprusside can cause a 
slight tingling sensation.  There are no known short- or long-term risks of 
CMR, and patients with pacemakers or other implants that are not MRI-
compatible will not be studied.  The CMR technique is noisy which can cause 
some discomfort to the subject; earplugs will be provided, and the subject 
can request that the scan be stopped at any time. Skin biopsies can be 
painful at the site although this is usually minor, and there is a risk of 
persistent bleeding and/or location infection.  The neuropathy evaluations do 
not pose any substantial risk or discomfort.  The monofilaments are plastic, 
and produce a very mild vibratory stimulus.  Blood draws or skin biopsies 
can sometimes elicit a vasovagal response with some dizziness or 
lightheadedness, which will be closely monitored by a licensed physician who 
will be present.  Risks of exercise testing include fatigue and muscle strain, 
and in extreme cases, abnormal blood pressure/heart rate responses.  Due 
to the need for vascular testing to take place in a fasting state, there is a 
risk of hypoglycemia particularly amongst the DM patients.  However, we are 
only studying patients with well-controlled DM, and subjects will be closely 
supervised by a licensed physician during testing.  CPAP treatment has no 
major side effects although some patients may experience anxiety and/or 
local skin irritation caused by the mask interface.  Sham CPAP is noisier than 
active CPAP which may lead to further daytime sleepiness or fatigue beyond 
that caused by untreated OSA.  Individuals will be cautioned against drowsy 
driving. 
 
Subjects with a high likelihood of OSA would likely undergo a diagnostic 
sleep study (at home or in-laboratory) and CPAP titration (either manual or 
using auto-PAP) as part of standard clinical care.  All other procedures 
outlined here are solely for research purposes.   
 

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The PI and co-investigators are certified in the research ethics training 
program offered by the Collaborative Institutional Training Initiative (CITI).  
All staff members of the Sleep Laboratory are trained in the responsible 
conduct 
of 
research, 
confidentiality 
issues 
and 
optimal 
data 
storage/acquisition methods.  The potential risk to the patients regarding 
privacy and confidentiality are minimal. 
 
EXPECTED BENEFITS 
Describe both the expected benefits to individual subjects participating in the research and the 
importance of the knowledge that may reasonably be expected to result from the study.  Provide 
a brief, realistic summary of potential benefits to subjects, for example, “It is hoped that the 
treatment will result in a partial reduction in tumor size in at least 25% of the enrolled subjects.”  
Indicate how the results of the study will benefit future patients with the disease/condition being 
studied and/or society, e.g., through increased knowledge of human physiology or behavior, 
improved safety, or technological advances. 
 
There are no direct benefits to the patients or healthy controls enrolling in 
this study.  Patients treated with active CPAP during Aim 2 are likely to 
experience a marked reduction in overnight symptoms of OSA, which will 
then likely to lead to improved long-term health. 
 
Results of the study will likely benefit future patients suffering from both 
OSA and DM, highlighting OSA as a potential treatment target to improve 
vascular functioning.  Currently, few patients with DM undergo investigation 
for co-morbid OSA despite the high prevalence of patients with both 
conditions.  Treatment of OSA among these patients will almost certainly 
reduce ongoing cardiovascular morbidity and mortality. 
 
EQUITABLE SELECTION OF SUBJECTS 
The risks and benefits of the research must be fairly distributed among the populations that stand 
to benefit from it.  No group of persons, for example, men, women, pregnant women, children, 
and minorities, should be categorically excluded from the research without a good scientific or 
ethical reason to do so.  Please provide the basis for concluding that the study population is 
representative of the population that stands to potentially benefit from this research.
 
Both men and women will be recruited, although we expect that males will 
outnumber females in the OSA groups, due to the higher prevalence of OSA 
amongst males.   
 
We expect the proportion of minorities to represent those in the New 
England area.  All potentially eligible subjects will be considered for inclusion 
regardless of race, ethnicity, or nationality. 
 
The risk factors for OSA are different between children and adults, and CPAP 
is not the first-line treatment for OSA in children.  Individuals under 18 
years of age will therefore be excluded.  The difference in endothelial 

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function between OSA patients and controls is not obvious beyond the age of 
50; we will ensure that a range of ages are recruited to investigate this 
further. 
 
Finally, OSA can occur during pregnancy due to other risk factors occurring 
during this period, and there is also a paucity of safety data concerning the 
vascular measurements undertaken during pregnancy.  We therefore plan to 
exclude pregnant women. 
 
When people who do not speak English are excluded from participation in the research, provide 
the scientific rationale for doing so.  Individuals who do not speak English should not be denied 
participation in research simply because it is inconvenient to translate the consent form in 
different languages and to have an interpreter present.
 
Subjects who do not speak English will be excluded, as the battery of 
questionnaires is in English.  These have not been validated for use in other 
languages. 
 
For guidance, refer to the following Partners policy: 
          Obtaining and Documenting Informed Consent of Subjects who do not Speak English
          http://healthcare.partners.org/phsirb/nonengco.htm 
 
 
 
RECRUITMENT PROCEDURES 
Explain in detail the specific methodology that will be used to recruit subjects.  Specifically 
address how, when, where and by whom subjects will be identified and approached about 
participation.  Include any specific recruitment methods used to enhance recruitment of women 
and minorities.
 
Subjects will be recruited from the community, using advertisements on 
bulletin boards, local newspapers, newsletters, websites, and email 
broadcasts including the phone number of the co-investigator/s.  Flyers will 
be placed at the Joslin Diabetes Center. 
 
OSA and DM patients will be recruited from local clinics.  Advertisements will 
be displayed in the clinic areas, alternatively potential patients may be 
approached by their sleep / DM physician.  The physician will either give the 
phone number of a potential subject to the co-investigator/s, or provide the 
phone number of the co-investigator/s to the subject.  Our research 
assistant will access medical records in order to determine which patients 
with upcoming appointments are eligible for the study, and communicate 
this information with the appropriate physician.  Only information that is 
necessary to determine eligibility will be accessed (demographics, problem 
list, medication list, clinic notes and results if needed).   

Partners Human Subjects Research Application Form 
 
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
14 
 
 
We will also use clinical and research lists from both Partners Healthcare 
(‘RPDR’) and Beth Israel Deaconess Medical Center (‘Clinical Query’) to send 
mail-outs to patients seen by physicians that we approach for their approval.   
 
Potentially eligible subjects will first call a research assistant who will discuss 
the eligibility criteria, study procedures, risks, time commitments, and 
potential benefits as outlined in the consent form.  Subjects will be 
encouraged to ask questions.  If interested, a consent form will be sent in 
the mail to all eligible subjects, who will have at least 24 hours consideration 
time before attending the screening visit.  A co-investigator will attend the 
screening visit in order to discuss the study procedures, risks and benefits 
face-to-face before obtaining consent. 
 
Provide details of remuneration, when applicable.  Even when subjects may derive medical 
benefit from participation, it is often the case that extra hospital visits, meals at the hospital, 
parking fees or other inconveniences will result in additional out-of-pocket expenses related to 
study participation.  Investigators may wish to consider providing reimbursement for such 
expenses when funding is available
 
Participants enrolling in Aim 1 will receive up to $200: $50 for completion 
of the sleep studies, $100 for completion of vascular testing, and $50 for 
completion of the MRI. 
 
Participants enrolling in Aim 2 will receive an additional $400: $300 for 
completion of the 3-month trial and vascular testing, and $100 for 
completion of the 2nd MRI. 
 
If a participant completes only the screening visit, they will receive $25. 
 
In addition, taxis will be provided free of charge to all patients if 
necessary following the sleep study.  Parking costs will also be 
reimbursed.   
 
For guidance, refer to the following Partners policies: 
          Recruitment of Research Subjects 
          http://healthcare.partners.org/phsirb/recruit.htm
 
          Guidelines for Advertisements for Recruiting Subjects
          http://healthcare.partners.org/phsirb/advert.htm
 
          Remuneration for Research Subjects
          http://healthcare.partners.org/phsirb/remun.htm
 
 

Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
15 
CONSENT PROCEDURES 
Explain in detail how, when, where, and by whom consent is obtained, and the timing of consent 
(i.e., how long subjects will be given to consider participation).  For most studies involving more 
than minimal risk and all studies involving investigational drugs/devices, a licensed physician 
investigator must obtain informed consent.  When subjects are to be enrolled from among the 
investigators’ own patients, describe how the potential for coercion will be avoided.
 
All potential subjects will have at least 24 hours to consider participation 
from receiving the consent form in the mail, to attendance at the screening 
visit.  As mentioned above, a co-investigator will be present at the screening 
visit to outline the study procedure, risks/benefits and time commitments 
before obtaining written informed consent.   
 
NOTE: When subjects are unable to give consent due to age (minors) or impaired decision-
making capacity, complete the forms for Research Involving Children as Subjects of Research 
and/or Research Involving Individuals with Impaired Decision-making Capacity, available on 
the New Submissions page on the PHRC website: 
http://healthcare.partners.org/phsirb/newapp.htm#Newapp
 
For guidance, refer to the following Partners policy: 
          Informed Consent of Research Subjects
          http://healthcare.partners.org/phsirb/infcons.htm
 
 
 
DATA AND SAFETY MONITORING 
Describe the plan for monitoring the data to ensure the safety of subjects.  The plan should 
include a brief description of (1) the safety and/or efficacy data that will be reviewed; (2) the 
planned frequency of review; and (3) who will be responsible for this review and for determining 
whether the research should be altered or stopped.  Include a brief description of any stopping 
rules for the study, when appropriate.  Depending upon the risk, size and complexity of the 
study, the investigator, an expert group, an independent Data and Safety Monitoring Board 
(DSMB) or others might be assigned primary responsibility for this monitoring activity.        
 
NOTE: Regardless of data and safety monitoring plans by the sponsor or others, the principal 
investigator is ultimately responsible for protecting the rights, safety, and welfare of subjects 
under his/her care. 
 
We will have a weekly meeting, directed by Dr. Bakker, during which we will 
review and monitor all of the data.  These meetings will include collaborators 
with expertise in DM (Dr. Aris Veves) and CMR (Dr. Raymond Kwong).  Dr. 
Bakker will be responsible for this review and for determining any alteration 
or termination of the study.  The study will be stopped if any unexpected 
adverse events are found that threaten general health and well-being of 
study subjects. 
 

Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
16 
Describe the plan to be followed by the Principal Investigator/study staff for review of adverse 
events experienced by subjects under his/her care, and when applicable, for review of sponsor 
safety reports and DSMB reports.  Describe the plan for reporting adverse events to the sponsor 
and the Partners’ IRB and, when applicable, for submitting sponsor safety reports and DSMB 
reports to the Partners’ IRBs.  When the investigator is also the sponsor of the IND/IDE, include 
the plan for reporting of adverse events to the FDA and, when applicable, to investigators at 
other sites.   
 
NOTE: In addition to the adverse event reporting requirements of the sponsor, the principal 
investigator must follow the Partners Human Research Committee guidelines for Adverse Event 
Reporting
 
Dr. Bakker will monitor and review adverse events in study subjects.  All 
adverse events possibly related to study interventions will be reviewed in 
weekly meetings and any serious adverse event/s related to the study 
procedures will be promptly reported according to PHRC policy: 
 (http://healthcare.partners.org/phsirb/adverse_events.htm).   
 
MONITORING AND QUALITY ASSURANCE 
Describe the plan to be followed by the principal investigator/study staff to monitor and assure 
the validity and integrity of the data and adherence to the IRB-approved protocol.  Specify who 
will be responsible for monitoring, and the planned frequency of monitoring.  For example, 
specify who will review the accuracy and completeness of case report form entries, source 
documents, and informed consent.   
 
NOTE: Regardless of monitoring plans by the sponsor or others, the principal investigator is 
ultimately responsible for ensuring that the study is conducted at his/her investigative site in 
accordance with the IRB-approved protocol, and applicable regulations and requirements of the 
IRB.
 
Dr. Jessie Bakker will be present during the consent procedure, and all data 
collection periods.  This will ensure that the study protocol is followed, and 
quality data are obtained.  All data will be reviewed at a bi-annual meeting 
of the co-investigators. 
 
For guidance, refer to the following Partners policies: 
          Data and Safety Monitoring Plans and Quality Assurance
          http://healthcare.partners.org/phsirb/datasafe.htm
 
          Adverse Event Reporting Guidelines
          http://healthcare.partners.org/phsirb/adverse_events.htm
 
 
 

Partners Human Subjects Research Application Form 
 
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
17 
 
PRIVACY AND CONFIDENTIALITY 
Describe methods used to protect the privacy of subjects and maintain confidentiality of data 
collected.  This typically includes such practices as substituting codes for names and/or medical 
record numbers; removing face sheets or other identifiers from completed 
surveys/questionnaires; proper disposal of printed computer data; limited access to study data; 
use of password-protected computer databases; training for research staff on the importance of 
confidentiality of data, and storing research records in a secure location.   
 
NOTE: Additional measures, such as obtaining a Certificate of Confidentiality, should be 
considered and are strongly encouraged when the research involves the collection of sensitive 
data, such as sexual, criminal or illegal behaviors.
 
All records are maintained confidential with only the investigators and 
technicians involved having access to the information.  The subject’s data 
will be coded by unique numbers so as to maintain both confidentiality, and 
blinding during data analysis.  The study staff and investigators will be 
careful to preserve patient confidentiality under all circumstances. 
 
With the permission of the subject, data collected that has direct clinical 
relevance (for example, sleep study data and blood work) will be compiled 
and forwarded to the relevant clinician. 
 
SENDING SPECIMENS/DATA TO RESEARCH COLLABORATORS OUTSIDE 
PARTNERS 
Specimens or data collected by Partners investigators will be sent to research collaborators 
outside Partners, indicate to whom specimens/data will be sent, what information will be sent, 
and whether the specimens/data will contain identifiers that could be used by the outside 
collaborators to link the specimens/data to individual subjects.
 
All procedures except circulation function testing and MRI will be conducted 
in Partners sites.  The subject will be given a different medical record 
number at BIDMC and the same identifier number as being used at BWH will 
be used also for BIDMC testing. 
De-identified skin biopsy slides will be sent to a pathology laboratory in 
Greece for analysis. 
De-identified skin biopsy slides will be sent to a laboratory in Germany for 
analysis. 
De-identified skin biopsy slides will be sent to a laboratory within BIDMC for 
analysis. 
 
Specifically address whether specimens/data will be stored at collaborating sites outside 
Partners for future use not described in the protocol.  Include whether subjects can withdraw 
their specimens/data, and how they would do so.  When appropriate, submit documentation of 
IRB approval from the recipient institution.
 

Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
18 
The testing done at BIDMC will only be used for the purpose of this study, 
and will not be used for any other purpose not described in this protocol.  
Subjects will be allowed to withdraw their specimens or data at any time by 
contacting the study investigators. 
 
RECEIVING SPECIMENS/DATA FROM RESEARCH COLLABORATORS OUTSIDE 
PARTNERS 
When specimens or data collected by research collaborators outside Partners will be sent to 
Partners investigators, indicate from where the specimens/data will be obtained and whether the 
specimens/data will contain identifiers that could be used by Partners investigators to link the 
specimens/data to individual subjects.  When appropriate, submit documentation of IRB 
approval and a copy of the IRB-approved consent form from the institution where the 
specimens/data were collected.
 
The data from testing conducted at BIDMC will be labeled with the same 
subject identifier as used in the tests done at BWH.