CPAP to Treat Cognitive Dysfunction in MS

August 18, 2022 updated by: Tiffany J. Braley, MD, MS, University of Michigan

A Randomized Trial of Positive Airway Pressure Therapy to Treat Cognitive Dysfunction in MS Patients With Obstructive Sleep Apnea

The objectives of this study are to determine the effects of obstructive sleep apnea (OSA) on cognitive function in patients with multiple sclerosis (MS); and to evaluate whether OSA treatment with positive airway pressure therapy could improve cognitive dysfunction in MS patients who have OSA.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Up to 70% of patients with MS suffer from cognitive dysfunction (difficulties with thinking, information processing, verbal expression, or memory). Cognitive dysfunction is one of the most disabling symptoms of MS, that can profoundly affect job performance, family responsibilities, and quality of life. While no treatments have been shown to improve cognitive dysfunction in MS, many patients have not been evaluated or treated for other common health problems that could be contributing to their cognitive dysfunction.

Up to 50% of MS patients also suffer from obstructive sleep apnea (OSA). Obstructive sleep apnea is a common disorder in which the upper airway collapses during sleep, causing poor sleep quality and decreased oxygen levels in the blood. In patients without MS, OSA is a well-established cause of poor cognitive performance. Recent studies of non-MS patients also suggest that cognitive performance may improve with OSA treatment. Yet, despite the high number of MS patients with OSA, the relationship between OSA and cognitive performance, and the effects of OSA treatment on cognitive performance in MS, has not received sufficient study.

The objectives of this study are to determine the effects of obstructive sleep apnea (OSA) on cognitive function in patients with multiple sclerosis (MS); and to evaluate whether OSA treatment with positive airway pressure therapy could improve cognitive dysfunction in MS patients who also have OSA.

Interested participants with MS who screen positive on a commonly used screening tool used to detect those at high risk for OSA will be invited to participate. Consenting participants will have a baseline cognitive (memory and thinking) test to assess their cognitive function, and an overnight sleep study (polysomnogram, or PSG) to determine if they have obstructive sleep apnea. If the sleep study shows signs of sleep apnea, participants will be assigned treatment for their sleep apnea with positive airway pressure (PAP) therapy, either immediately (Group 1), or 3 months after the baseline sleep study (Group 2). Groups will be assigned at random (like flipping a coin). There is a 2/3 chance that participants will be assigned to Group 1. 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. In order to determine which airway pressure most effectively treats an individual's sleep apnea, and what type of mask is needed, a separate sleep study known as an overnight "PAP titration study" will also be performed. This study is similar to a PSG but also involves fitting of various masks which are then hooked up to the individual and PAP machine to test the effectiveness of various PAP settings, and to determine which mask is most tolerable for the individual.

Participants will also receive repeat cognitive testing at 3 months to see if the immediate sleep apnea treatment group (Group 1) shows improvements memory and thinking, as compared to the standard care treatment group (Group 2), who will not start apnea treatment until after their repeat cognitive test. Participants will be compensated for their travel and time throughout the course of the study.

Study Type

Interventional

Enrollment (Actual)

135

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Michigan
      • Ann Arbor, Michigan, United States, 48109
        • University of Michigan Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 68 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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).

    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

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Other
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Immediate PAP therapy (Group 1)
Subjects will receive PAP treatment for OSA as soon as possible after baseline PSG and repeat baseline cognitive testing 3 months after initiation of PAP therapy. 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 your apnea severity, and the supplied air pressure can be continuous or change with your breathing pattern (bilevel).
Device: PAP therapy
Positive airway pressure treatment for obstructive sleep apnea
Other Names:
  • CPAP
  • BiPAP
  • Continuous positive airway pressure
  • Positive airway pressure
  • Bi-level positive airway pressure
Other: Standard Care PAP therapy (Group 2)
Subjects will delay PAP treatment for 3 months following their baseline sleep study, and repeat their baseline cognitive testing prior to PAP treatment for sleep apnea. 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 your apnea severity, and the supplied air pressure can be continuous or change with your breathing pattern (bilevel).
Device: PAP therapy
Positive airway pressure treatment for obstructive sleep apnea
Other Names:
  • CPAP
  • BiPAP
  • Continuous positive airway pressure
  • Positive airway pressure
  • Bi-level positive airway pressure

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Association Between Obstructive Sleep Apnea (OSA) Severity [as Measured by Apnea Hypopnea Index (AHI) e.g., Number of Apneic Events Per Hour of Sleep] and Baseline Performance on the Minimal Assessment of Cognitive Function in MS Battery (MACFIMS)
Time Frame: Participants had up to 3 weeks to complete both baseline cognitive testing and PSG

Bivariate associations between AHI measured with PSG, and baseline MACFIMS test results which include:

  • Controlled Oral Word Association Test (COWAT): verbal fluency;
  • Judgement of Line Orientation test (JLO): visuospatial perception;
  • Brief Visuospatial Memory Test Revised Total (BVMT-R Total) and Brief Visuospatial Memory Test Revised Delayed (BVMT-R Delayed): visual memory & learning;
  • California Verbal Learning Test-II Total score (CVLT-II): verbal memory & learning;
  • Paced Auditory Serial Addition Test-2 (PASAT-2), Paced Auditory Serial Addition Test-3 (PASAT-3) and Symbol Digit Modalities test (SDMT): memory, attention, processing speed.

For each test higher scores indicate better cognitive performance. Beta coefficients were generated with multiple linear regression models, yielding the confidence intervals shown below.
Participants had up to 3 weeks to complete both baseline cognitive testing and PSG
Change From Baseline in Performance on the Minimal Assessment of Cognitive Function in MS Battery (MACFIMS)
Time Frame: baseline, 3 months

Mean change in scores on individual MACFIMS tests from baseline to month 3 cognitive testing, as calculated by Month 3 minus baseline score shown by treatment group. MACFIMS tests with score ranges (minimum-maximum) are listed here:

  • Controlled Oral Word Association Test (COWAT) 0 - no recognized upper limit;
  • Judgement of Line Orientation test (JLO) 0-34 based on scores adjusted for age and sex;
  • Brief Visuospatial Memory Test Revised Total (BVMT-R Total) 0-36;
  • Brief Visuospatial Memory Test Revised Delayed (BVMT-R Delayed), 0-12;
  • California Verbal Learning Test-II Total score (CVLT-II); (T scores necessary for analysis; 50=population mean; 10=SD);
  • Paced Auditory Serial Addition Test-2 (PASAT-2), 0-60;
  • Paced Auditory Serial Addition Test-3 (PASAT-3) 0-60; and
  • Symbol Digit Modalities test (SDMT) 0-110. For all measures, higher scores mean better performance, so based on subtracting 3 month values minus baseline, any positive numbers indicate improvement.
baseline, 3 months

Other Outcome Measures

Outcome Measure
Time Frame
Association Between Polysomnographic Measures of Sleep Efficiency (Ratio of Time Spent Asleep to Total Time in Bed) and Baseline Performance on the Minimal Assessment of Cognitive Function in MS Battery (MACFIMS)
Time Frame: 3 weeks
3 weeks
Association Between Wake Time After Sleep Onset (Total Time in Minutes Spent Awake After Sleep Onset, and Before Final Awakening Time) and Baseline Performance on the Minimal Assessment of Cognitive Function in MS Battery (MACFIMS)
Time Frame: 3 weeks
3 weeks
Association Between the Total Arousal Index (Average Number of EEG Arousals Per Hour of Sleep) and Baseline Performance on the Minimal Assessment of Cognitive Function in MS Battery (MACFIMS)
Time Frame: 3 weeks
3 weeks
Association Between Sleep Stage Percentages (% Total Sleep Time Spent in Stage N1, N2, N3, and REM Sleep) and Baseline Performance on the Minimal Assessment of Cognitive Function in MS Battery (MACFIMS)
Time Frame: 3 weeks
3 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Michigan

Collaborators

National Multiple Sclerosis Society

Investigators

  • Principal Investigator: Tiffany Braley, MD, MS, University of Michigan

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 12, 2015

Primary Completion (Actual)

June 25, 2021

Study Completion (Actual)

June 25, 2021

Study Registration Dates

First Submitted

May 26, 2015

First Submitted That Met QC Criteria

September 4, 2015

First Posted (Estimate)

September 9, 2015

Study Record Updates

Last Update Posted (Actual)

September 14, 2022

Last Update Submitted That Met QC Criteria

August 18, 2022

Last Verified

August 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HUM00098738

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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