A Randomized Trial of Positive Airway Pressure Therapy to Treat Cognitive Dysfunction in MS Patients With Obstructive Sleep Apnea
Phase: NA
Conditions: Multiple Sclerosis
Sponsor: University of Michigan

 
Title:  A Randomized Trial of Positive Airway Pressure Therapy to Treat 
Cognitive Dysfunction in MS Patients with Obstructive Sleep Apnea 
 
 
PI:  Tiffany Braley, MD, MS 
 
ID: HUM00098738  
 
NCT:  NCT02544373 
 
IRB Approval Date: 8/13/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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A Randomized Trial of Positive Airway Pressure Therapy to Treat Cognitive 
Dysfunction in MS Patients with Obstructive Sleep Apnea 
 
Version 9.0 6/6/19 
 
 
HUM00098738 
Phase: 4 
Institution:   
 
University of Michigan 
Principal Investigator:  
Tiffany J. Braley, MD, MS 
Co-Investigators:  
 
Ronald D. Chervin MD, MS 
Joseph W. Burns, Ph.D 
Anna L. Kratz, Ph.D 
 
 

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TABLE OF CONTENTS 
 
PROTOCOL SUMMARY………………………..………………………………………….. 
4 
1.  INTRODUCTION……………………………………………………………………........ 
7 
1.1 Indication ……………………………………………………………………….……..… 
7 
1.2 Background and Rationale …………………………………………………………….… 
7 
1.3 Safety………………………………………………………………………………….… 
8 
2.  STUDY OBJECTIVES AND ENDPOINTS………………………………………….... 
11 
2.1 Objectives ……………………………………………………………………………… 
11 
2.2 Endpoints……………………………………………………………………………….. 
11 
3.  STUDY DESIGN……………………………………………………………………..….. 
12 
4.  SUBJECT SELECTION…………………………………………………………….….. 
13 
4.0 Subject Recruitment……………………………………………………………………. 
13 
4.1 Inclusion Criteria………………………………………………………………………… 
13 
4.2 Exclusion Criteria……………………………………………………………….………. 
14 
5.  STUDY TREATMENTS…………………………………………………………..…….. 
15 
5.1 Allocation to Treatment………………………………………………………………… 
15 
5.2 Blinding…………………………………………………………………………..……… 
15 
5.3 Study Treatment with Positive Airway Pressure Therapy…………………..………..… 
15 
6.  STUDY PROCEDURES………………………………………………………….…….. 
16 
6.1 Screening/Baseline visit………………………………………………………………... 
16 
6.2 Cognitive Testing………………………………………………………………………. 
16 
6.3 Baseline PSG visit……………………………………………………………………… 
18 
6.4 Randomization………………………………………………………………………….. 
19 
6.5 PAP titration……………………………………………………………………............. 
20 
6.6 Month 1 and Month 2 Follow-up Visits …………………………………………..….... 
20 
6.7 Month 3 Visit with repeat Cognitive Testing………………………………………...... 
20 
6.8 Post-Study Follow-up phone assessment for Group 2………………………..…………. 
21 
SCHEDULE OF ACTIVITIES TABLE…………………………………………………..…. 
22 
7.  ASSESSMENTS……………………………………………………………………..…... 
23 
7.1 Primary Endpoint Assessments………………………………………………………..… 
23 
7.2 Exploratory Assessments…………………………………………………..... 
23 
7.2.1 General Medical History……………………….……………………………………….. 
24 
7.2.2 Concomitant Medication Use………………………………………………………..… 
24 
7.2.3 Adverse Events………………………………………………………………………….. 
24 
8.  ADVERSE EVENT REPORTING……………………………………………............. 
24 
9.  DATA ANALYSIS/STATISTICAL METHODS……………………………………….. 
24 
9.1 Sample Size Determination…………………………………………………………….... 
24 
9.2 Analysis of Primary Endpoint………………………………………………………..….. 
25 
9.3 Analysis of Exploratory Endpoints…………………………………………… 
25 
10.  MONITORING…………………………………………………………………………... 
25 
10.1 Data Safety Monitoring Plan…………………………………………………………….. 
25 

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10.2 Monitoring Plan and Information……………………………………………………..... 
26 
11.  DATA HANDLING AND RECORD KEEPING……………………………………… 
26 
11.1 CRFs / Electronic Data Record……………………………………………………….... 
26 
11.2 Record Retention……………………………………………………………………..… 
26 
12.  ETHICS………………………………………………………………………………... 
26 
12.1 IRB…………………………………………………………………………………..…. 
26 
12.2 Subject Information and Consent ………………………………………………….….. 
26 
13.  STUDY DISCONTINUATION CRITERIA………………………………………… 
27 
14.  REFERENCES………………………………………………………………………… 
28 
 
 
 
 
 
 

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PROTOCOL SUMMARY  
 
Background and Rationale 
Multiple sclerosis (MS) is a chronic, autoimmune disease that causes inflammation and 
destruction of the brain and spinal cord.  This condition is the leading cause of non-traumatic 
disability among young adults, and affects nearly half a million Americans and 2.5 million 
people worldwide.  In addition to physical disability, MS patients suffer disproportionately from 
a variety of complications that negatively impact quality of life, including cognitive dysfunction, 
and sleep disturbances. 
 
Cognitive dysfunction is one of the most common and consequential symptoms of MS.  
Impairments in processing speed, working memory, learning, executive function, visual-spatial 
processing, and language function affect 42-70% of MS patients, and constitute a major cause of 
loss of employment, caregiver stress, and reduced quality of life.1-5  Despite the high prevalence 
and consequences of cognitive dysfunction in MS, the identification of appropriate strategies to 
minimize its impact is hindered by a poor understanding of factors that influence its severity, or 
common medical comorbidities that may increase patients’ vulnerability to its effects.   
 
Obstructive sleep apnea (OSA) is a common disorder characterized by repeated episodes of 
upper airway obstruction during sleep. Growing evidence suggests that nocturnal hypoxia caused 
by OSA contributes to cognitive dysfunction in the general population,6-10 and that treatment for 
OSA in the form of positive airway pressure (PAP) therapy may improve cognitive dysfunction 
in individuals who do not have MS.11, 12  Yet, the relationship between cognition and sleep apnea 
remains virtually unstudied in patients with MS.  This is a critical gap in knowledge, as our 
recent data suggest that at least one fifth of MS patients carry a diagnosis of OSA, while a 
substantially higher proportion of patients (more than half) may have undiagnosed OSA.  
Furthermore, new data from our group suggest that OSA severity is closely related to reductions 
in cognitive performance in MS subjects.13  These preliminary findings indicate that OSA could 
contribute to domains of cognitive dysfunction that are key aspects of morbidity in MS.  Larger, 
prospective studies are now needed to demonstrate the nature and directionality of the 
relationship between sleep disordered breathing and cognitive dysfunction in individuals with 
MS.  If a causal role does exist, identification and treatment of OSA could provide new 
opportunities improve cognition in persons with MS.   
 
Objectives, Aims, and Endpoints 
The objectives of this randomized, rater-blinded clinical trial are to 1) determine the effects of 
OSA on specific domains of cognitive function in patients with MS; and 2) assess the effects of 
OSA treatment with positive airway pressure (PAP) therapy on cognitive dysfunction in MS 
patients. 
 
For Aim 1, subjects with MS (n~175) who screen positive on a commonly used screening tool 
for OSA (STOP-Bang questionnaire)14 or who have a preexisting diagnosis of OSA but are not 
yet using PAP compliantly will undergo baseline cognitive testing and standard nocturnal 
polysomnography (PSG). For subjects who have a recent diagnosis of OSA based on recent 
(within 1 year) in-lab clinical University of Michigan Sleep Laboratory PSG who have not yet 
started using PAP treatment compliantly, their in-lab clinical PSG data will be used for baseline 

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analyses.  After adjustment for clinical confounds and other PSG outcomes, we will assess the 
extent to which apnea severity as reflected by baseline PSG contributes to cognitive dysfunction 
in MS.   
 
For Aim 2, subjects who meet criteria for OSA on baseline PSG or recent U-M Sleep Lab in-lab 
clinical PSG (n~140) will be randomized into one of 2 groups: expedited positive airway 
pressure (PAP) therapy, followed by repeat cognitive testing at 3 months post-PAP (Group 1, 
n~93), or standard care PAP therapy which will commence following completion of month 3 
testing (Group 2, n~47).  Mean changes from baseline in cognitive test scores will be compared 
between groups.   
 
Assessments 
The aims of this study are to assess the relationship between sleep apnea severity and cognitive 
dysfunction in MS patients with OSA (Aim 1), and to examine the effects of positive airway 
pressure (PAP) on cognitive function in MS patients with OSA (Aim 2).   
 
N~175 patients who screen positive for high OSA risk on a validated screening questionnaire 
(STOP-Bang), or who already carry a diagnosis of OSA but are not yet using PAP on a 
compliant basis will be invited to participate.   
 
Consenting subjects with STOP-Bang scores positive for >=2 risk factors for sleep apnea who 
are at high risk for OSA but who do not yet have a University of Michigan Sleep Laboratory 
PSG will undergo baseline (month 0) in-lab PSG and baseline neuropsychological (cognitive) 
testing.  Subjects who have a recent diagnosis of OSA based on recent (within 1 year) in-lab 
clinical University of Michigan Sleep Laboratory PSG who have not yet started using PAP 
treatment compliantly will undergo baseline cognitive testing and their in-lab clinical PSG data 
will be used for baseline analyses.  Subjects who have a diagnosis of OSA based on non-UM in-
lab PSG or PSG > 1 year prior to screening will undergo new baseline PSG and baseline 
cognitive testing. 
 
Subjects who meet criteria for OSA on baseline or clinical PSG (n~140, anticipated) will then be 
randomized into one of 2 groups (2:1 randomization): immediate treatment with PAP (Group 1, 
n~93) followed by repeat neuropsychological testing at 3 months post-PAP; or standard of care 
application of PAP at 3 months, after completion of repeat neuropsychological testing (Group 2, 
n~47).  Analyses will focus on relationships between standard PSG measures (including the 
Respiratory Disturbance Index, oxygen desaturation index, and minimum oxygen saturation), 
innovative new quantitative PSG measures and cognitive test scores, as well as mean changes 
from baseline in individual and composite cognitive test scores following treatment with PAP 
therapy. 
 
Statistical Methods  
Analyses will focus on relationships between standard PSG measures (Respiratory Disturbance 
Index, oxygen desaturation index, and minimum oxygen saturation), innovative new quantitative 
PSG measures and cognitive test scores, as well as mean changes from baseline in individual 
cognitive scores following treatment with PAP therapy. 
 

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For aim 1, multivariate linear regression models will be used to analyze the effects of PSG-
derived standard measures of sleep disordered breathing (including RDI, ODI, minimum O2 
saturation), on individual cognitive test scores (continuous outcome variables of interest, in 
separate models).  For Aim 2, multivariate linear regression models will be used to test the 
effects of Group effect on 3-month (“post”) cognitive test scores, controlling for baseline (“pre”) 
test scores and other covariates.  We will also examine the association of PAP use as a 
continuous variable, based on mean nightly hours of use per month, on 3-month individual 
cognitive test scores, controlling for baseline scores.

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1. INTRODUCTION 
 
1.1 Indication 
The proposed study will assess the relationship between obstructive sleep apnea severity and 
cognitive dysfunction in MS patients with OSA (Aim 1), and examine the effects of positive 
airway pressure (PAP) on cognitive function in MS patients with OSA (Aim 2). 
 
1.2 Background and Rationale  
 
Cognitive dysfunction is one of the most common and disabling consequences of multiple 
sclerosis.    
Multiple sclerosis (MS) is a chronic, autoimmune disease that causes inflammation and 
destruction of the brain and spinal cord.  In addition to physical disability, MS patients suffer 
disproportionately from a variety of complications that negatively impact quality of life, 
including cognitive dysfunction. 
 
Cognitive dysfunction is one of the most consequential symptoms of MS, spanning multiple 
domains of function including processing speed, working memory, learning, executive function, 
visual-spatial processing, and language function.  It is experienced by 42-70% of MS patients 
and is a major cause of loss of employment, caregiver stress, and reduced quality of life.1-5  
Compared to individuals with MS who report only physical impairments, those with cognitive 
impairments are more likely to be unemployed and suffer from a mental illness, less likely to 
engage in social or vocational activities, and have more difficulty carrying out some activities of 
daily living. Even individuals with MS who are not considered to be “cognitively impaired” per 
se, and those whose functioning may remain in the normal range, may experience mild to 
moderate declines in cognitive functioning which could contribute to distress and functional 
impairments.  Despite its impact, there are no definitive treatments for cognitive dysfunction in 
MS.  While cognitive rehabilitation in MS may help to enhance information processing and 
general level of function, this approach is still considered relatively new, and its utility remains 
under investigation.  Adjunctive treatments aimed at improving cognitive functioning are sorely 
needed.   Furthermore, the identification of appropriate strategies to prevent and remediate 
cognitive dysfunction in MS is hindered by a poor understanding of clinical features that may 
influence its severity, or comorbidities that may increase patients’ vulnerability to its effects.  
Further efforts are needed to identify and address clinical factors that could cause or exacerbate 
cognitive dysfunction in MS, and to identify patients who are most vulnerable to these effects. 
 
Obstructive sleep apnea (OSA) is a common and consequential medical disorder that 
causes cognitive dysfunction in the general population.   
Obstructive sleep apnea (OSA) is a common disorder of sleep and breathing.  The condition is 
characterized by repeated episodes of upper airway obstruction, hypoxia, and arousal during 
sleep.  This growing epidemic is estimated to affect 10-20% of Americans, and is a well-
recognized risk factor for many serious health consequences including hypertension, stroke, 
heart disease, and diabetes.15, 16 Obstructive sleep apnea also carries a profound societal impact 
in the form of daytime sleepiness, lost productivity, and absenteeism in the workplace.17, 18  The 
first-line treatment for OSA, Positive Airway Pressure (PAP), which is delivered by a 
mechanical device and mask interface, splints the upper airway open during sleep and effectively 

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ameliorates many of the symptoms caused by OSA.  This air pressure can be continuous 
(CPAP), bi-level (BiPAP), or auto-adjusting (AutoPAP). 
 
Obstructive sleep apnea is also an established cause of cognitive dysfunction in the general 
population.6-9, 11, 12 10 Sustained intermittent hypoxia that arises from OSA in non-MS patients 
has been linked to myelin and axonal injury, gray matter atrophy, as well as impaired executive 
function, long-term visual and verbal memory, visuospatial/constructional abilities, and 
attention.11, 19, 20 21, 22  Furthermore, treatment of OSA with PAP therapy has been shown to 
improve executive dysfunction, delayed long-term verbal and visual memory, 
attention/vigilance, global cognitive functioning, and gray matter volume in OSA patients 
without MS, but the effect of OSA and its treatment with PAP therapy has not been studied in the 
context of comorbid MS. 
 
Clinical Rationale 
Whereas the detrimental effects of OSA on cognition are well-established in the general 
population, the relationship between OSA and cognition has been virtually unstudied in patients 
with MS - a population that is particularly vulnerable to myelin and axonal damage by virtue of 
their neurological condition.  This is a clinically relevant intersection, as MS is associated with a 
disproportionately high prevalence of OSA: new data from a recent study at our clinics show that 
at least 20% of MS patients suffer from clinically definite OSA, and up to 56% are at risk for 
OSA based on a validated screening tool (STOP-Bang).23, 24   
 
Furthermore, preliminary findings from the investigators suggest that sleep disturbances, and 
OSA in particular, could contribute to domains of cognitive dysfunction that are key aspects of 
morbidity in MS.  If a causal role does exist, identification and treatment of OSA could provide 
new opportunities to improve cognition in MS patients.  This study will for the first time 
prospectively evaluate the effects of OSA severity and its treatment on multiple key 
domains of cognitive function most affected in patients with MS, while controlling for other 
sleep- and MS-related variables that may influence these relationships. 
 
Hypotheses 
Hypothesis 1: Sleep apnea severity, as reflected by standard PSG measures [respiratory 
disturbance index (RDI), oxygen desaturation index (ODI), and minimum oxygen saturation 
(Min O2)], as well as innovative new quantitative approaches, will be associated with reduced 
MACFIMS scores.  
 
Hypothesis 2: Group 1, in comparison to Group 2, will show greater improvement from baseline 
in MACFIMS scores, on repeat MACFIMS testing at month 3. 
 
1.3 Safety  
 
Risks 
This study presents minimal potential risks to participants. There are no alternatives to 
these data collection procedures. Participants may choose to not participate in any part of this 
voluntary study. Potential risks include: Discomfort during completion of study questionnaires or 

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cognitive testing, and/or discomfort related to sleep studies or wearing PSG equipment. The 
study team will take all reasonable steps to minimize these risks. 
 
Study Questionnaires: The questionnaire battery, which requires the participants to reflect upon 
and report on their physical and emotional symptoms may cause mild emotional distress. 
Baseline and follow up questionnaires are expected to take approximately 30 minutes on 
average; during this time, participants may experience physical pain, fatigue, or boredom. 
Participants will have the option to take breaks and may elect to complete the questionnaires on 
another day if they are too tired or distressed. In addition, the names and contact information of 
the study team will be noted on the consent form and participants can contact them if needed. 
 
Cognitive Testing: Cognitive testing is expected to take the average participant approximately 90 
minutes to complete. During that time, it is possible that the participant may experience 
discomfort in the form of fatigue, physical pain, or boredom. In addition, if the participant 
perceives that they are not performing well, they may feel frustrated or emotionally distressed. 
The examiner who administers the cognitive tests will monitor the participant for signs of 
discomfort and distress and, as needed, will offer breaks and/or encouragement in the form of 
normalizing any emotional distress. In the event that a participant becomes extremely physically 
or emotionally uncomfortable, he or she may elect to discontinue testing or continue the 
remainder of the testing on another day. 
 
In-laboratory overnight Polysomnography (sleep study) and Positive Airway Pressure (PAP) 
titration:  The baseline sleep study (PSG) should not be painful and generally has few 
complications. Sensors or electrodes are placed on the scalp, face, chest, limbs, and a finger.  The 
equipment records brain activity, eye movements, chin muscle activity, heart rate and rhythm, 
blood pressure, and the amount of oxygen in your blood.  Elastic belts are placed around the 
chest and belly to measure chest movements and the strength and duration of inhaled and 
exhaled breaths. Additional sensors will measure airflow at the nose and mouth.  Wires attached 
to the sensors transmit the data to a computer in the next room. The wires are very thin and 
flexible. They are bundled together so they don't restrict movement, disrupt sleep, or cause other 
discomfort. The most common side effect is mild irritation where electrodes come in contact 
with the skin. It may also be stressful to sleep away from the comfort of the subject’s normal 
sleep environment. Subjects may sleep poorly in the lab, and as a result feel sleepy on the day 
after the study. For this reason, subjects are encouraged to ask someone to drive them to the 
sleep laboratory and take them home on the next morning.  Skin integrity is checked by the sleep 
technologists.  If subjects have a skin reaction at the site of a sensor used to monitor sleep or 
heart rate, the technologist will move it to another site and use a different type of tape or glue. If 
subject’s skin should become irritated at multiple sites or in any severe manner, the study will be 
stopped. Any skin irritation at sites where sensors were placed is expected to resolve after the 
study on its own, usually in hours or at most a day or two.  
 
Unless already performed for clinical purposes at U-M Sleep lab within the past year, 
participants who are diagnosed with OSA on baseline PSG will then undergo PAP titrations* to 
determine the ideal PAP machine setting(s), and participants will be prescribed clinical CPAP or 
BiPAP machines by clinicians involved in the study or their clinical sleep provider.   
 

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PAP therapy is considered standard clinical care for OSA.  It involves wearing an apparatus that 
includes a hose and a mask (that covers the nose, or nose and mouth), connected to a small 
machine that blows air into the airway during sleep. The degree of air pressure given depends on 
the subject’s apnea severity, and the supplied air pressure can be continuous or change with the 
subject’s breathing pattern.  This in-laboratory PAP titration sleep test uses the same sensors and 
has the same complications as the baseline sleep study, but the subject will also wear a mask 
attached to a PAP machine during sleep for this test, so that the sleep technicians can determine 
which type of mask and airway pressure are most appropriate. Masks can be uncomfortable and 
create a feeling of claustrophobia.  Air pressure may dry out nasal passages. Subjects will be 
encouraged to alert the staff in the sleep laboratory to any other concerns, discomfort, or 
complications that arise during the PSG or PAP titration. A doctor will always be on call for any 
unexpected health emergencies. 
 
*In some cases, insurance carriers will not cover the cost of an in-laboratory PAP titration, and 
instead will recommend an “auto-adjusting” PAP machine (also known as AutoPAP, or APAP) 
so that patients diagnosed with OSA may begin PAP without requiring a PAP titration.  
AutoPAP differs from a CPAP in that it uses algorithms to sense subtle changes in the user's 
breathing and deliver only the amount of pressure necessary to keep the airway open.  AutoPAP 
can be also set to a straight CPAP mode, if determined necessary by the sleep provider, therefore 
offering more flexibility than a CPAP or BiPAP machine.  In cases where AutoPAP is 
recommended by the participant’s insurance carrier and no medical or PSG contraindications to 
AutoPAP exist, participants will be allowed to waive their in-lab PAP titration and start 
AutoPAP therapy according to their PAP randomization assignment. 
 
PAP Therapy:  There may be skin irritation related to the PAP mask, and masks can be 
uncomfortable and create a feeling of claustrophobia. There are multiple choices and sizes for 
sleep masks, and the provider will work with the subjects to find the most comfortable mask. 
There may be difficulty tolerating the forced air, but the pressure settings can be adjusted by 
working with the sleep machine provider. Subjects might experience a dry stuffy nose which can 
be treated with a saline nasal spray or humidified air that can be run through the PAP machine. 
The providers of these machines are very familiar with resolutions to and they will try and assist 
subjects in order to resolve any issues. 
 
Confidentiality:  The records of this study will remain confidential and protected; however, there 
is a risk for a breach of confidentiality. This risk is minimal, because a number of precautions 
have been taken in order to protect confidentiality. All data collected will be kept secure and in a 
locked office. Records will be coded and identifying information (such as name and registration 
numbers) will be removed and stored on a key in a separate location so that confidential 
information cannot be traced back to the subject. Only authorized members of the research team 
will have access to study records. 
 
Standard care PAP treatment arm (for Group 2):  Given that most consequences of OSA take 
months to years to manifest (cardiovascular disease, metabolic syndrome), we do not anticipate 
any significant long-term side effects from deferring PAP for 3 months for Group 2.  
Identification of sleep disordered breathing will be facilitated by enrollment into this study. 
Nonetheless, to avoid hazardous short-term consequences of OSA caused by excessive 

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sleepiness (e.g., motor vehicle accidents), ESS scores >= 16 on baseline or follow-up visits will 
be cause for study exclusion/discontinuation.  This cutoff was chosen based on data that 
demonstrate an ordinal increase in risk of sleepy driving accidents with increases in ESS score, 
particularly in subjects with ESS scores > 15.  We will also consider extreme OSA (RDI>60 
respiratory events per hour, or unstable ECG rhythms on PSG) to be exclusionary, regardless of 
ESS score. For subjects who are not considered to be high risk per these criteria, we do not 
expect the risk of participating in this trial and having no CPAP for 3 months to exceed the risk 
encountered in routine clinical practice, as wait times for sleep clinic evaluations, subsequent 
sleep clinic referral, PSG, CPAP titration, and CPAP initiation at home currently often amount to 
3 months or longer at U-M sleep clinics. 
 
 
Alternative treatments and procedures:  This study does not include an intervention. Therefore, 
there are no applicable alternative treatments or procedures.  
 
As with any research study, there may be additional risks that are unforeseeable.  
 
 
 
2.  STUDY OBJECTIVES AND ENDPOINTS 
 
2.1 Objectives 
The objectives of this randomized, rater-blinded clinical trial are to 1) determine the effects of 
OSA on specific domains of cognitive function in patients with MS; and 2) assess the effects of 
OSA treatment with positive airway pressure (PAP) therapy on cognitive dysfunction in MS 
patients. 
 
2.2 Endpoints 
2.2.1 Primary Endpoint(s) 
Effects of PSG-derived standard measures of sleep disordered breathing (including RDI, 
ODI, minimum O2 saturation), on cognitive test scores. 
 
Effects of PAP therapy on cognition, as measured by mean change from baseline in cognitive 
test scores in Group 1 (expedited PAP therapy) compared to Group 2 (delayed PAP therapy).  
 
2.2.2 ExploratoryEndpoints 
Effects of standard and novel PSG-derived measures of sleep disturbances (including TST, 
WASO, TAI, SE, RCREC, and sleep stage dynamics) on cognitive test scores. 
 
Mean change from baseline in subjective sleepiness, as measured by the Epworth Sleepiness 
Scale, in group 1 vs group 2;  
 
Mean change from baseline in daytime fatigue level, as measured by the Fatigue Severity 
Scale, in group 1 vs group 2; 
 
Mean change from baseline in insomnia level, as measured by the Insomnia Severity Index, 
in group 1 vs group 2; 

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Mean change from baseline in quality of life and chronic daily symptoms (fatigue, anxiety, 
pain) as assessed by the Patient Reported Outcomes Measurement Information System 
(PROMIS, www.nihpromis.org/), in group 1 vs group 2. 
 
3.  STUDY DESIGN  
N~175 patients who screen positive for high OSA risk on a validated screening questionnaire 
(STOP-Bang) given during routine MS Clinic appointments at the University of Michigan will 
be invited to participate. Additional subjects may be recruited from the community through a U-
M electronic clinical trials registry (UMclinicalstudies.org); a clinicaltrials.gov posting; print or 
electronic newspaper advertisement; fliers at the medical center and in the community; and from 
study advertisements posted by the University of Michigan on Facebook and Twitter.  Potential 
subjects who contact the study staff directly, or are referred by outside providers, and have not 
completed a STOP-Bang questionnaire, will be asked the STOP-Bang questions via telephone 
during a pre-screening interview.  If their STOP-Bang assessment indicates a risk for sleep apnea 
(score >=2 risk factors for sleep apnea), they will be invited to participate.  If their STOP-Bang 
score is below a 2, they will not be eligible for the study.   
 
Subjects who endorse a pre-existing diagnosis of OSA who are not yet using PAP therapy on a 
compliant basis - but who express an interest to start using it - will also be invited to participate.  
 
Consenting subjects with elevated STOP-Bang scores or those who are at high risk for OSA will 
undergo baseline (month 0) PSG and baseline neuropsychological testing (MACFIMS) (see 
figure).  Subjects who already have recent U-M in-lab PSG (within 1 year) indicating OSA will 
also undergo baseline cognitive testing, and their in-lab clinical PSG data will be used for 
baseline analyses.  Subjects who have a diagnosis of OSA based on non-UM lab PSG or PSG > 1 
year prior to screening will undergo baseline PSG and baseline cognitive testing. 
 
Subjects who meet criteria for OSA on baseline or clinical in-lab PSG (n~140, anticipated) 
will then be randomized into one of two groups (2:1 randomization): immediate treatment 
with PAP (Group 1, n~93) followed by repeat neuropsychological testing at 3 months post-
PAP; or standard of care application of PAP at 3 months post-randomization, after 
completion of repeat neuropsychological testing (Group 2, n~47).  Analyses will focus on 
relationships between standard PSG measures (Respiratory Disturbance Index, oxygen 
desaturation index, and minimum oxygen saturation), innovative new quantitative PSG measures 
and MACFIMS scores, as well as mean changes from baseline in individual and composite 
MACFIMS scores following treatment with PAP therapy. 

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4.  SUBJECT SELECTION 
 
4.0 Subject Recruitment 
The projected number of subjects for enrollment is N~175, all diagnosed with clinically definite 
MS.  Subjects will be recruited from the University of Michigan (U-M) MS Clinic during routine 
appointments.  An additional recruitment site will include a new, first-of-its-kind Sleep and MS 
Multidisciplinary Clinic, founded by the investigators (Drs. Braley and Chervin).  Additional 
subjects may be recruited from the community through a U-M electronic clinical trials registry 
(UMclinicalstudies.org); a clinicaltrials.gov posting; print or electronic newspaper 
advertisement; fliers at the medical center and in the community; and from study advertisements 
posted by the University of Michigan on Facebook and Twitter.  Information on the study will 
also be available via letter to medical colleagues in the community, advertised on a posted flyer, 
advertised via the internet through the UM research recruiting website 
(https://umclinicalstudies.org), advertised on a registry of clinical trials run by the United States 
National Library of Medicine (NLM) at the National Institutes of Health (clincicaltrials.gov), and 
advertised on Craigslist.  
 
4.1 Inclusion Criteria 
1)  Age of 18-70 years at screening  
2)  Diagnosis of clinically definite MS  
3)  Willingness to undergo in-lab baseline polysomnography (PSG) and positive airway pressure 
(PAP) titration (if needed) 
4)  Willingness to undergo 2 separate 90-minute cognitive testing sessions  
5)  Either one of the following: 
Score of >=2 sleep apnea risk factors on the "STOP-Bang" sleep apnea screening 
questionnaire. The STOP-Bang questionnaire is a screening tool consisting of eight 
items which reflect OSA risk factors.  STOP-Bang scores of ≥3 indicate elevated risk for 
moderate-severe OSA in the general population, and scores as low as 2 are frequently 
seen in MS patients with OSA, based on previous data from the PI).   
 

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OR 
 
Have a pre-existing diagnosis of OSA based on a previous overnight sleep study 
(either home study or in-lab) but have not yet started using PAP therapy on a compliant 
basis.  *If OSA was NOT diagnosed by a U-M in-lab sleep study within the past year 
prior to screening, subjects must be willing to get new baseline in-lab U-M PSG as part 
of study. 
 
6)  Willingness to start treatment with PAP if OSA present 
 
4.2 Exclusion Criteria 
1)   Physical, psychiatric or cognitive impairment that prevents informed consent, PSG, PAP use, 
or reliable longitudinal follow-up 
2)   Cardiopulmonary conditions that may increase sleep apnea risk  
3)   Current treatment, such as PAP, for obstructive or central sleep apnea  
4)   History of surgical treatment for OSA  
5)   Nervous system diseases other than MS that may predispose subjects to OSA (such as 
Parkinson's disease, amyotrophic lateral sclerosis, or recent stroke)  
6)    History of concomitant central nervous system disease that could influence cognition, such 
as large vessel territory stroke, Alzheimer’s disease, Parkinson’s disease, or Lewy body 
dementia 
7)    Concomitant systemic autoimmune disease with secondary central nervous system 
        involvement (including CNS lupus or neurosarcoidosis). 
8)    Pregnancy  
9)    Evidence of clinical MS relapse within the last 30 days prior to enrollment 
10)  Systemic high dose steroid use (1 gram IV methylprednisolone daily for 3-5 days or  
        equivalent)for an MS relapse within the last 30 days prior to enrollment 
11)  Unwillingness to initiate PAP therapy if clinically indicated  
12)  Severe depression at screening per the Patient Health Questionnaire-8 (PHQ-8)  
(The PHQ-8 is a brief, self-administered questionnaire that evaluates core symptoms 
associated with major depressive disorder.  Scores range from 0 to 24 based on the 
frequency and severity of depressive symptoms over the previous two weeks.)  
13)  Anticipated initiation, dosage change, or discontinuation in medications that could, per the 
opinion of the investigators, influence cognitive test scores from baseline to follow-up, 
including MS disease modifying therapies, hypnotic agents, narcotic-based medications, 
benzodiazepines, antispasmodics, or 4-aminopyridine 
14)  ESS scores >= 16 on baseline visit 
15)  Subjects with extreme OSA accompanied by signs of cardiopulmonary compromise 
(RDI>60 respiratory events per hour with severe nocturnal hypoxia or unstable ECG 
rhythms on PSG), will be excluded unless they are randomized to immediate PAP arm 
16)  Any other condition or treatment that in the opinion of the investigator could affect subject 
safety or study eligibility 

Page 16 of 30 
 
 
 
Table 1: STOP-Bang questionnaire 
Snoring 
Do you snore loudly (louder than talking or loud enough to be heard 
through closed doors)? 
Tired 
Do you often feel tired, fatigued, or sleepy during the daytime? 
Observed Apneas 
Has anyone ever observed you stop breathing during your sleep? 
Blood Pressure 
Do you have or are you being treated for high blood pressure? 
BMI 
BMI more than 35 kg/m2? 
Age 
Age over 50 years old? 
Neck circumference 
Are you a male with a neck circumference greater than 17 inches, or a female 
with a neck circumference greater than 16 inches? 
Gender 
Are you a male? 
 
 
5.  STUDY TREATMENTS 
 
5.1 Allocation to Treatment (see also 6.4) 
Randomization Process: Subjects who meet all Inclusion/Exclusion criteria, including OSA on 
baseline or clinical PSG, will be randomized (2:1 randomization) to expedited PAP therapy 
(Group 1, n~93), or standard care PAP therapy (Group 2, n~47), after the subject has signed 
consent, completed the baseline activities, Randomization will be stratified by sleep apnea 
severity (RDI < or >=30) to minimize imbalances in apnea severity between groups.  
 
5.2 Blinding 
PSG technicians, PSG interpreters, and study staff who conduct and score neuropsychological 
tests will remain blinded to group allocation for the duration of the study. The subject, PI, co-
investigators, coordinators, and statistician will not be blinded. 
 
5.3 Treatment with Positive Airway Pressure (PAP) Therapy: Unless already performed at 
U-M sleep lab within the past year, all subjects who are diagnosed with OSA on baseline or 
clinical PSG (n~140) will undergo PAP titrations* and be prescribed clinical PAP therapy by 
clinicians involved in the study or the subject’s treating sleep provider.  PAP therapy is 
considered standard clinical care for patients with obstructive sleep apnea. PAP is a mode of 
respiratory ventilation that blows air into the nose (or nose and mouth) to splint the upper airway 
open during sleep. PAP therapy can be delivered at a continuous pressure (CPAP), at different 
levels during inspiration and expiration (BiPAP), or at a range of auto-adjustable levels 
depending on the patient’s breathing (AutoPAP)*.  In order to determine which pressure setting 
most effectively treats an individual’s sleep apnea, an overnight PAP titration study is typically 
required.  This study is similar to a PSG in terms of overnight monitoring but also involves 
fitting of various masks which are then hooked up to the subject and PAP machine to test the 
effectiveness of various PAP settings, and to determine which mask/setting is most tolerable for 
the subject.  PAP titration studies will be scored by certified PSG technologists and interpreted 
by a board-certified sleep physician, who will then place an order for PAP equipment at 
appropriate settings with a local durable medical equipment (DME) provider. DME will be 
covered by the subject’s insurance.   

Page 17 of 30 
 
 
* In some cases, insurance carriers will not cover the cost of an in-laboratory PAP titration, and 
instead will recommend an “auto-adjusting” PAP machine (also known as AutoPAP, or APAP) 
so that patients diagnosed with OSA may begin PAP without requiring a PAP titration.  
AutoPAP differs from a CPAP in that it uses algorithms to sense subtle changes in the user's 
breathing and deliver only the amount of pressure necessary to keep the airway open.  In cases 
where AutoPAP is recommended by the participant’s insurance carrier and no medical or PSG 
contraindications to AutoPAP exist, participants will be allowed to waive their in-lab PAP 
titration and start AutoPAP therapy according to their PAP randomization assignment. 
 
6.  STUDY PROCEDURES 
 
6.1 Screening/Baseline Visit 
Subjects will be seen at one of several University of Michigan clinical or research study sites for 
baseline visit activities, including but not limited to the Michigan Clinical Research Unit 
(MCRU), or the Department of Neuropsychology testing suite in the Med-Inn Building.  
Inclusion and Exclusion Criteria will be reviewed, and informed consent will be obtained by 
qualified study staff.  Consenting subjects who meet eligibility criteria at screening will be 
enrolled and receive their baseline evaluation, where they will undergo the following 
assessments:  
 
1)  Demographic information 
2)  Focused medical and surgical history as it relates to multiple sclerosis, sleep, and 
cardiopulmonary history 
3)  Medication review  
4)  Assessments of height, weight, and neck circumference 
5)  Expanded Disability Status Scale self-report questionnaire  
(a self-reported measure of MS-related disability)  
6)  Pregnancy test (for females of childbearing age) 
(if a pregnancy test was performed within the past month, that result may be 
used and the test does not need to be repeated) 
7)  Fatigue, insomnia, and sleepiness assessments (see 7.2) 
8)  Pain, anxiety, and quality of life assessments (see 7.2)  
9) Baseline neuropsychological testing (see 6.2)* 
10) Unless already done clinically at U-M sleep lab within the past year, baseline 
polysomnography (PSG, see 6.3) 
 
 
*If subjects are unable to complete baseline neuropsychological testing on the day of 
their baseline visit, this will be scheduled within 3 weeks of screening/baseline visit.  
 
6.2 Cognitive (Neuropsychological) Testing 
The Minimal Assessment of Cognitive Function in MS (MACFIMS)26, 27 is a validated, 90-
minute neuropsychological battery comprised of a collection of standardized cognitive tests 

Page 18 of 30 
 
which assess 5 main cognitive domains that are commonly affected in MS: processing 
speed/working memory, learning, executive function, visual-spatial processing, and language 
function, using 7 standard measures.  Endorsed by the Consortium of Multiple Sclerosis 
Specialists (CMSC), it is one of the most accepted neuropsychological batteries in the field.  All 
MACFIMS testing will be performed by blinded, trained psychometricians who are part of the 
pool of technicians in the department of Psychiatry at the University of Michigan. All 
psychometricians are directly supervised by an onsite Ph.D.-level neuropsychologist in 
Psychiatry; furthermore, Dr. Kratz, a clinical psychologist who is a co-investigator on this 
project will oversee all neuropsychological data collection and extraction.  Components of the 
MACFIMS, include in this study are as follows: 
 
Symbol Digit Modalities Test (SDMT): Consists of a series of 9 symbols paired with a single 
digit in a key at the top of an exam sheet.  Below the key, the remainder of the page consists 
of pseudo-randomized sequence of these symbols, and the examinee must recall the correct 
corresponding digit as quickly as possible, either by scanning the key, or using recall.  The 
final score consists of the total number of items correct within a 90 second testing interval. 
The oral administration will be used for this study. The Standard Form and Alternate Form 
of the SDMT will be used. 
 
Paced auditory serial addition test (PASAT): Patients listen to a series of audiotaped digits 
and must add each consecutive digit to the one immediately preceding it.  Digits presented at 
two different rates (every 2 seconds or 3 seconds).  Scores reflect the total number of correct 
responses at each presentation rate (PASAT-2 or PASAT-3). Two alternate forms, Form A 
and Form B, will used in this study.  
 
California Verbal Learning Test (CVLT-II): Subjects learn a 16-word list (list A), the recall 
of which is examined over a course of 5 trials.  Subjects are then asked to recall a new 16- 
word list (interference list, List B), after which time the original list is reassessed after a 25-
minute delay interval.  Total number of words recalled on trials 1-5 and delayed recall are 
scored. The CVLT-II has both a Standard Form and an Alternative form that will be used in 
this study.  
 
Brief Visuospatial Memory Test – Revised (BVMT-R): Assesses spatial learning and 
memory using a matrix of simple abstract designs presented in three trials (10 seconds each). 
Subjects are asked to recall (immediate and after a delay) and recognize the designs from 
distractor designs.  Form 1 and Form 2 will be used in this trial. 
 
Judgment of line orientation test (JLO): Measure of visual-spatial abilities.  Subjects are 
required to identify the angle defined by 2 stimulus lines, from those which are located in a 
visual array of lines that cover 180 degrees.  Scores reflect total number of correct responses.  
Form H and a Form V will be used in this study.  
 
Controlled word association test (COWAT): Measure of phonemic fluency, in which subjects 
are asked to name as many words as they can that begin with 3 different stimulus letters 
within 60 seconds.  Scores reflect total number of words generated across all 3 trials. Two 
alternate versions (CFL/PRW) of the COWAT will be used.  
 
Nine-hole Peg Test (NHPT): Using a standard NHPT board, subjects place plastic pegs into 9 
holes one at a time, and remove them one at a time as quickly as they can.  Test is scored as 

Page 19 of 30 
 
the time (seconds) it takes the subject to complete the task. Two trials on both dominate and 
non-dominate hands are completed.  
 
Trail Making Test (Part A and B): Both parts of the Trail Making Test consist of 25 circles 
distributed over a sheet of paper. In Part A, the circles are numbered 1 – 25, and the patient 
should draw lines to connect the numbers in ascending order. In Part B, the circles include 
both numbers (1 – 13) and letters (A – L); as in Part A, the patient draws lines to connect the 
circles in an ascending pattern, but with the added task of alternating between the numbers 
and letters (i.e., 1-A-2-B-3-C, etc.). The patient should be instructed to connect the circles as 
quickly as possible, without lifting the pen or pencil from the paper. Time the patient as he or 
she connects the "trail." Results for both TMT A and B are reported as the number of seconds 
required to complete the task; therefore, higher scores reveal greater impairment. 
 
The North American Adult Reading Test (NAART) - 35: The NAART is a widely used to 
estimate verbal intellectual ability/verbal intelligence.  The test consists of a list of 35 
irregularly pronounced English words.  The examinee is required to read each word, and their 
score is based on the number of correctly pronounced words (according to American and 
Canadian punctuation rules). Because scores on the NAART are thought to reflect basic 
aspects of crystalized intelligence and are not expected to change, this test will only be 
administered once – at baseline. 
 
Go/No-go test: The GNG task involves the presentation of letter stimuli one at a time every 
500 ms on the computer screen.  After a brief training session, participants are instructed to 
quickly press a button each time they see the target letters X, Y or Z: either 1) each time the 
target letters are presented (go trials), or only when the target letters are presented in 
alternating non-repeating fashion (no-go trials). Reaction time and accuracy are recorded. 
 
Two fixed batteries of these tests (see table 2 below) will be created. Order of administration of 
Fixed Test Battery A and Fixed Test Battery B will be randomized across subjects.   
 
Table 2: Cognitive batteries 
Test 
Fixed Test Battery A 
Fixed Test Battery B 
SDMT 
Standard Form 
Alternate Form 
PASAT 3 
Form A 
Form B 
PASAT 2 
Form A 
Form B 
CVLT-II 
Standard Form 
Alternate Form 
BVMT-R 
Form 1 
Form 2 
JLO 
Form H 
Form V 
COWAT 
CFL 
PRW 
NHPT 
Standard administration 
Standard Administration 
Trails A and B 
Standard form 
Alternative form 
NAART 
Standard Form – baseline 
only 
 
Standard form – baseline only 
Go/No-go test 
Standard administration 
Standard administration 
 
 
6.3 Baseline PSG visit* 

Page 20 of 30 
 
Conventional In-lab Overnight Polysomnography (PSG):  Procedures and scoring will follow the 
latest American Academy of Sleep Medicine Scoring Rules.28 Standard measures will include: 
total sleep time (TST), sleep efficiency, sleep latency (SL [minutes from lights out to first 30 
seconds of any sleep stage]), wake after sleep onset, total arousal index (TAI, average number of 
EEG arousals per hour of sleep), % total sleep time spent in stage 1, 2, 3, and REM sleep, the 
Respiratory Disturbance Index (RDI - total number of apneas, hypopneas and respiratory-related 
arousals per hour of sleep)central apnea index (total number of central apneas per hour of sleep), 
oxygen desaturation index (ODI, number of desaturation events >=3% below baseline oxygen 
saturation levels), minimum oxygen saturation (Min O2), and % of sleep time with O2 saturation 
≤ 88%.  PSG’s will be scored by a single, experienced, technologist, masked to treatment group.  
Scoring will be reviewed and confirmed, and studies interpreted, by a board-certified sleep 
specialist.   
 
Innovative PSG Signal Analysis Algorithms: In addition to conventional PSG measures, PSG 
data will also be analyzed using a novel PSG algorithm that has never been applied to sleep or 
cognitive research in MS patients. This will involve no changes to the subject’s overnight 
PSG procedure or experience.  This novel method, invented and patented by co-investigators 
Drs. Chervin and Burns,29, 30 uses variations in EEG power (for specific frequency bands) during 
discrete phases of the respiratory cycle (early expiration, late expiration, early inspiration, and 
late inspiration) to detect subtle, cortical microarousals not visible on standard visual inspection 
of the PSG.28-30  This algorithm will allow a more sensitive evaluation of potential effects that 
disordered nocturnal respiration could have on cerebral cortical function among MS patients.  
Specifically, respiratory cycle-related EEG changes (RCREC), which reflect cortical 
microarousals, will be computed to detect subtle disturbances in respiration beyond standard 
apnea/hypopnea measures, which will then be correlated with MACFIMS scores. 
 
The study team has also pioneered the application of analyses of sleep dynamics – temporal 
patterns of sleep stages rather than simpler total sums or percentages of stage 1, 2, 3, and REM 
sleep – to discriminate between disordered and normal sleep when standard measures fail to do 
so.  These techniques also will be applied to sleep recordings, to identify additional sleep-related 
predictors of cognitive dysfunction beyond conventional measures of nocturnal respiration in MS 
patients. 
 
*For subjects who have a recent diagnosis of OSA based on recent (within 1 year) clinical 
University of Michigan Sleep Laboratory PSG, these clinical PSG data will be used for the same 
baseline analyses above.   
 
6.4 Randomization 
Randomization Process/Blinding: Subjects who meet criteria for OSA on baseline or clinical 
PSG (n~140, anticipated) will be randomized (2:1 randomization) to determine whether they will 
receive expedited PAP therapy (Group 1, n~93), or standard of care PAP therapy (Group 2, 
n~47).  Computer-based randomization will be stratified by sleep apnea severity (RDI < or 
>=30) to minimize imbalances in apnea severity between groups. PSG technicians, PSG 
interpreters, and study staff who conduct and score neuropsychological tests will remain blinded 
to group allocation for the duration of the study. The subject, PI, co-investigators, coordinators, 
and statistician will not be blinded.  Subjects will be contacted with the randomization 

Page 21 of 30 
 
assignment that determines whether they will be scheduled for immediate PAP titration 
(Group 1) or delayed PAP titration after their month 3 cognitive testing. 
 
 
6.5 PAP titration  
(After randomization for Group 1, and following month 3 cognitive testing for Group 2) 
Standard AASM guidelines will be followed in laboratory-based PAP titration studies designed 
to determine effective continuous PAP (CPAP) or bilevel PAP (BiPAP) settings, when 
necessary, for subjects with OSA.  Studies will be scored by certified PSG technologists and 
interpreted by a board-certified sleep physician. Clinicians involved in the study or the subject’s 
treating sleep provider will then place an order for PAP equipment at appropriate settings with a 
local durable medical equipment (DME) provider. DME will be covered by the subject’s 
insurance.  The DME company will provide subjects with equipment, instruct them on proper 
use at home, and provide supplies as needed.  PAP titrations can be waived if subjects have had a 
recent U-M sleep lab clinical PAP titration within the past year. In cases where AutoPAP is 
recommended by the participant’s insurance carrier and no medical or PSG contraindications to 
AutoPAP exist, participants will be allowed to waive their in-lab PAP titration and start 
AutoPAP therapy according to their PAP randomization assignment. Adherence of PAP therapy 
will be monitored by electronic downloads or datacards within the PAP machines. 
 
 
6.6 Month 1 and Month 2 Follow-up Visits/Assessments  
Group 1:   1 and 2 months following PAP initiation – Group 1 subjects will have the 
option of doing their MONTH 2 assessment by phone or in person 
 
Group 2:   1 and 2 months following randomization – Group 2 subjects will have the 
option of doing either of these assessments by phone or in person 
 
All randomized subjects will undergo the following assessments: 
1)  Focused medical and surgical history as it relates to MS, sleep, and cardiopulmonary 
history 
2)  Medication review 
3)  PAP compliance review (datacard assessment) for Group 1  
4)  Fatigue, insomnia, and sleepiness assessments (see 7.2) 
5)  AE/SAE review  
 
6.7 Month 3 Visit with repeat Cognitive Testing  
Group 1:   3 months after PAP initiation 
Group 2:   3 months after randomization 
 
All randomized subjects will undergo the following assessments: 
1)  Focused medical and surgical history as it relates to MS, sleep, and cardiopulmonary 
history 
2)  Medication review  
3)  PAP compliance review for Group 1 
4)  Fatigue, insomnia, and sleepiness assessments (see 7.2) 

Page 22 of 30 
 
5)  Pain, anxiety, and quality of life assessments (see 7.2) 
6)  AE/SAE review 
7)  Repeat neuropsychological testing (see 6.2)  
8)  PAP titration for group 2 (if applicable)*   
 
* Group 2 subjects are encouraged to undergo PAP titration on the night of the Month 3 
visit.  If they agree to this approach, the PAP titration will be scheduled around the time 
of the Month 2 visit. 
 
6.8 Post-Study Follow-up phone assessment for Group 2 (1 month after Month 3 visit) 
Following the  Month 3 visit (and once the PAP titration is complete) , for Group 2 subjects who 
still express a desire to proceed with PAP treatment, the study team will contact the subject 
and/or DME company (phone or email) to confirm that a PAP prescription has been faxed to the 
subject’s designated DME company), and if applicable, that UM sleep clinic follow up has been 
made.  Three phone contacts will be attempted.  Any barriers to the PAP prescription process 
will be passed on to sleep clinic staff for appropriate action.  If no clinic follow up has been 
scheduled per the subject’s account (and the subject still desires a sleep clinic appointment), the 
study team will contact appropriate UM sleep clinic personnel to contact the subject.

Page 23 of 30 
 
SCHEDULE OF ACTIVITIES 
 
Study Activity 
Baseline Visit 
Baseline PSG visit 
Month 0 
Month 1 
Month 2 
Month 3 
Demographics 
X 
 
 
 
 
 
Medical/Surgical History 
X 
 
 
X 
X 
X 
Medication review 
X 
 
 
X 
X 
X 
Height, weight, neck 
circumference 
X 
 
 
 
 
 
EDSS self-report 
X 
 
 
 
 
 
AE/SAE review 
X 
 
 
X 
X 
X 
Baseline neuropsych testing 
(all subjects) 
X 
 
 
 
 
 
Repeat neuropsychological 
testing (OSA subjects) 
 
 
 
 
 
X 
Baseline PSG (all subjects 
who do not have U-M PSG 
within the past year) 
 
X 
 
 
 
 
Randomization (for subjects 
with OSA on baseline PSG) 
 
 
X 
 
 
 
PAP titration/prescription 
for Group 1 
 
 
X 
 
 
 
PAP compliance review 
for Group 1 
 
 
 
X 
X 
X 
Fatigue (FSS), insomnia 
(ISI), and sleepiness (ESS) 
surveys 
X 
 
 
X 
X 
X 
PROMIS/NeuroQOL 
measures 
X 
 
 
 
 
X 

Page 24 of 30 
 
7.  ASSESSMENTS  
 
7.1 Primary Endpoint Assessments 
Cognitive performance (primary outcome measure of interest) will be assessed with formal 
neuropsychological testing (see section 6.2).  Sleep apnea severity (primary predictor of interest) 
will be assessed with overnight polysomnography (see section 6.3). 
 
7.2 Exploratory 
Measures of sleep quality and sleep fragmentation, as well as Innovative PSG Signal Analysis 
Algorithms (secondary predictors of cognitive performance), will be assessed with overnight 
polysomnography (see section 6.3). 
 
Epworth Sleepiness Scale (ESS): The ESS is an 8-item questionnaire that asks about the 
likelihood of dozing in variably sedentary situations.31 This commonly used measure of 
subjective sleepiness, or sleep propensity, is reliable, internally consistent, and validated against 
objective polysomnographic measures.  A score ≥10 suggests excessive sleepiness. 
 
Krupp’s Fatigue Severity Scale (FSS): The FSS is a validated, 9-item instrument that measures 
the impact of fatigue on multiple outcomes, with a physical focus.32  Prior studies have shown 
acceptable internal consistency and stability over time, and sensitivity to change that correlates 
with the subject’s clinical improvement.  Many if not most past studies on MS-related fatigue 
have used the FSS.  
 
Insomnia Severity Index (ISI): The Insomnia Severity Index (ISI) is a 7-item questionnaire with 
5-point Likert scale responses designed to assess the nature, severity, and impact of insomnia in 
adults. 33 Scores of 15 or higher reflect moderate clinical insomnia.   
 
Patient Reported Outcomes Measurement Information System (PROMIS)/Quality of Life in 
Neurological Disorders (NeuroQol): The federally-funded Patient Reported Outcomes 
Measurement Information System (PROMIS) and Quality of Life in Neurological Disorders 
(NeuroQoL) are two integrated systems of highly reliable and responsive assessment tools that 
use modern measurement theory to assess patient-reported health related quality of life.  Using 
validated item banks and standardized metrics, PROMIS and NeuroQoL reliably measure 
patient-reported outcome measures (PROM’s) for clinical research.  PROMIS and NeuroQoL 
measures, derived from large question banks, can be given as static short forms (typically 7-8 
items in length).  Measures can be used as primary or secondary endpoints in clinical studies that 
assess treatment effect for multiple symptoms including quality of life, pain, anxiety, fatigue and 
sleep quality (www.nihpromis.org/; www.neruoqol.org). 
 
 
7.2.1 General Medical History 
General medical history will be assessed at baseline and in all follow-up visits.  Subjects will be 
queried about any chronic or ongoing health conditions that require treatment (which will be 
recorded in the CRF).  Subjects will also be asked to provide their list of medications and 
allergies. 
 
7.2.2 Concomitant Medication Use 

Page 25 of 30 
 
Concomitant medications will be assessed at each visit and/or phone contact and recorded in the 
CRF. 
 
7.2.3 Adverse Events 
Adverse events will be assessed at each visit by questioning subjects about any symptoms they 
have been experiencing while on the study. 
 
8.  ADVERSE EVENT REPORTING 
Multiple Sclerosis is a disease with many disease-related symptoms and complications, and there are 
many common mild side effects associated with PAP therapy.  Due to the patient population and the 
nature of the disease, as well as the lack of experimental interventions in this study (only standard of 
care procedures and treatments will be used) we would like to implement the following AE/SAE 
collection/reporting guidelines: 
 
SAE events that meet all 3 of the following criteria will be collected and submitted: 
•     Serious;  
•     Related; and 
•     Unanticipated 
 
In addition, the following AEs will be collected and submitted: 
 
•     Any AE that results in a change to research 
 
9.0 DATA ANALYSIS/STATISTICAL METHODS 
 
9.1 Sample Size Determination 
Estimates (means and standard deviations) are derived from our recent data that evaluated 
SDMT scores among MS subjects referred for overnight PSG, and previously published 
interventional studies in that evaluated the effects of medical interventions on components of the 
MACFIMS in MS patients. We have chosen to focus on SDMT score as the primary outcome 
variable of interest, as the SDMT encompasses multiple domains of cognitive function, is 
frequently used in MS clinical studies as a reliable measure of cognitive impairment, and is 
sensitive to changes in intervention.   
 
Based on a power analysis of two sample means (unequal sample sizes, with 2:1 randomization) 
with a 0.05 two-sided significance level, and an estimated S.D. of 9, a total sample size of 140 
subjects will have an 86.3% power to detect a 5-point difference in SDMT score between groups, 
on month 3 testing, for hypothesis 2.  Similarly, using individual MACFIMS components as 
outcome variables (in separate models), a multiple linear regression power analysis shows that a 
sample size of n=140 subjects will yield 88% power to detect an R-square difference of 0.05 for 
the test predictor of interest (% PAP use per month, as a continuous measure), assuming the R-
squared explained by the adjustment variables is at least 0.3.   
 
Although we predict a low dropout rate due to the short duration of the study, if we assume a 
dropout rate of 15% (10 dropouts per group), we will still have a power of 81.2% power to detect 
a 5-point difference in SDMT score between groups, on month 3 testing.   
 
9.2 Analysis of Primary Endpoint 

Page 26 of 30 
 
Aim 1: Multivariate linear regression models will be used to analyze the effects of baseline PSG-
derived standard measures of sleep disordered breathing (including RDI, ODI, minimum O2 
saturation), on individual cognitive test scores (continuous outcome variables of interest, in 
separate models) for Aim 1, controlling for other sleep, serological, and clinical variables. 
Additional models that use computed respiratory cycle-related EEG changes (calculated as the 
maximum difference between the mean EEG powers associated with each of the 4 respiratory 
cycle segments as predictor variables) will be used to evaluate the effects of respiratory-related 
cortical microarousals on cognitive test scores, controlling for other clinical and sleep-related 
variables.  Separate models that use computed temporal patterns of sleep stages as predictors of 
cognitive test scores will also be constructed. 
 
Aim 2: Multivariate linear regression models will be used to test the effects of Group effect on 3-
month (“post”) cognitive test scores, controlling for baseline (“pre”) test scores.  We will also 
examine the association of PAP use as a continuous variable, based on mean nightly hours of use 
per month, on 3-month individual cognitive test scores, controlling for baseline scores. Separate 
models will be used for each cognitive test of interest. Predictor variables that are unbalanced 
between groups despite randomization will be used as covariates in the analyses. 
 
To evaluate early effects of PAP therapy on cognitive scores, sleep stage dynamics will also be 
assessed during PAP titrations to determine whether changes in sleep stage stability predict 
improvements on cognitive test scores in separate models. 
 
9.3 Analysis of exploratory endpoints 
Multiple linear regression models will be used to assess the effect of PAP treatment effect 
(Group 1 vs. Group 2 effect) on tertiary outcome measures including daytime sleepiness (ESS 
scores), fatigue (FSS, PROMIS scores), and anxiety, pain, and quality of life (PROMIS scores).   
 
10. MONITORING 
 
10.1 Data Safety Monitoring Plan 
Monitoring of the study will be conducted by a qualified clinical trial monitor according to an 
established monitoring plan.  All subjects who are diagnosed with OSA will also be overseen by 
a certified sleep provider throughout the duration of the study, who will then continue to follow 
them once study activities have ceased.  Subjects who are not already established patients in the 
U-M MS/sleep clinic will be referred for expedited sleep clinic follow up following their PSG 
diagnosis of OSA.  Whenever possible, these clinical visits will occur in tandem with study 
visits. 
 
Although none of the measures in this study assess self-harm, in the event that a participant 
mentions suicidal ideation or other severe mental distress that could result in harm to self or 
others, Dr. Anna Kratz (Co-Investigator), who is a licensed psychologist, will contact the 
participant by phone and complete a standard self-harm/suicide assessment, taking appropriate 
action (e.g. referral for mental health services, contacting emergency services) as needed.  All 
safety related incidents will be reported to the PI and the IRB according to relevant protocols.  
 
10.2 Monitoring Plan and Information  

Page 27 of 30 
 
To assure adequate protection of the rights of human subjects, per 21 CFR 312.50 and 312.53, 
the study will be monitored to ensure that the study is implemented in accordance with the 
protocol and applicable federal and local regulations, that proper informed consent procedures 
were followed and to insure the integrity and quality of the data. 
 
A qualified trial monitor will be selected, per 21 CFR 312.53(d) to monitor the trial in 
accordance with the protocol and all applicable regulatory requirements.  A monitoring plan will 
be established to ensure the quality and integrity of the data through pre-investigation, periodic 
site visits, review of adverse events/subject records, etc.  The Michigan Institute for Clinical and 
Health Research (MICHR) will assist with the selection and support of the monitor assigned for 
this proposed clinical investigation and prepare the monitoring plan.  
 
11.  DATA HANDLING AND RECORD KEEPING 
 
11.1 CRFs / Electronic Data Record 
CRFs, in paper or electronic format, will be utilized and maintained by the study staff.  Entries 
made in the CRF must be verifiable against source documents, unless the CRF is considered to 
be the source document.   
 
11.2 Record Retention 
Per 21 CRF §312.62, study records will be retained for a minimum of 7 years after the 
investigation is discontinued. 
 
12.  ETHICS 
 
12.1 IRB 
Prior to study commencement, the study will be reviewed and approved by the Institutional 
Review Board (IRBMED, University of Michigan, Ann Arbor, MI). 
 
12.2 Subject Information and Consent 
A study team member will explain to each subject the nature of the study, its purpose, the 
procedures involved, the expected duration, the potential risks and benefits involved and any 
discomfort it may entail.  Each subject will be informed that participation in the study is 
voluntary and that he/she may withdraw from the study at any time and that withdrawal of 
consent will not affect his/her subsequent medical treatment or relationship with the treating 
physician. 
 
This informed consent will be given by means of a standard written statement, written in non-
technical language. The subject should read and consider the statement before signing and dating 
it, and should be given a copy of the signed document. No patient can enter the study before 
his/her informed consent has been obtained. 
 
The informed consent form is considered to be part of the protocol, and will be submitted for 
IRB approval. 
 
13.  STUDY DISCONTINUATION CRITERIA 

Page 28 of 30 
 
 
Stopping Rules for Safety Reasons 
Subjects who demonstrate evidence of severe excessive daytime sleepiness (as evidenced by ESS 
scores >= 16 at baseline) will result in exclusion from study.  Subjects with extreme OSA that is 
accompanied by signs of cardiopulmonary compromise or severe nocturnal hypoxia on baseline 
PSG will also result in study exclusion unless they are randomized to expedited PAP arm.  In 
such cases, subjects will be referred for expedited sleep clinic follow-up. 
 
Discontinuation of a Subject 
In the event a patient drops out of the study or is discontinued due to protocol violations, all 
attempts will be made to exit the patient in accordance with the protocol requirements. 
 

Page 29 of 30 
 
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