Multiple Sclerosis
Conditions
Keywords
OSA, Obstructive Sleep Apnea, Cognition, Cognitive Dysfunction, Memory, Positive Aiway Pressure, CPAP, MS
Brief summary
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.
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.
Interventions
DEVICEPAP therapy
Positive airway pressure treatment for obstructive sleep apnea
Sponsors
National Multiple Sclerosis Society
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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) | 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. |
| Change From Baseline in Performance on the Minimal Assessment of Cognitive Function in MS Battery (MACFIMS) | 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. |
Other
| 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) | 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) | 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) | 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) | 3 weeks |
Countries
United States
Participant flow
Pre-assignment details
Of 135 enrolled participants,131 received both baseline cognitive testing and polysomnography for Aim 1 (pre-intervention) analyses (outside of the interventional phase of the study. Among these 131 participants, 111 were randomized for this trial.
Participants by arm
| Arm | Count |
|---|---|
| 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).
PAP therapy: Positive airway pressure treatment for obstructive sleep apnea | 71 |
| 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).
PAP therapy: Positive airway pressure treatment for obstructive sleep apnea | 40 |
| Total | 111 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 5 | 3 |
| Overall Study | Withdrawal by Subject | 8 | 2 |
Baseline characteristics
| Characteristic | Immediate PAP Therapy (Group 1) | Standard Care PAP Therapy (Group 2) | Total |
|---|---|---|---|
| Age, Continuous | 48.9 years STANDARD_DEVIATION 9 | 49.2 years STANDARD_DEVIATION 9.2 | 49.0 years STANDARD_DEVIATION 9 |
| Apnea Hypopnea Index | 23.1113 units on a scale STANDARD_DEVIATION 19.22115 | 20.4875 units on a scale STANDARD_DEVIATION 16.30875 | 22.1658 units on a scale STANDARD_DEVIATION 18.19362 |
| Race/Ethnicity, Customized American Indian/Alaskan Native | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 8 Participants | 5 Participants | 13 Participants |
| Race/Ethnicity, Customized Hispanic | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized Non-Hispanic | 69 Participants | 37 Participants | 106 Participants |
| Race/Ethnicity, Customized Unknown/Not reported | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 61 Participants | 33 Participants | 94 Participants |
| Region of Enrollment United States | 71 Participants | 40 Participants | 111 Participants |
| Sex: Female, Male Female | 50 Participants | 28 Participants | 78 Participants |
| Sex: Female, Male Male | 21 Participants | 12 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 71 | 0 / 40 |
| other Total, other adverse events | 11 / 71 | 0 / 40 |
| serious Total, serious adverse events | 0 / 71 | 0 / 40 |
Outcome results
Primary
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)
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.
Time frame: Participants had up to 3 weeks to complete both baseline cognitive testing and PSG
Population: These analyses were conducted to examine associations between apnea severity and cognitive performance prior to randomization and PAP intervention. Four out of 135 consented had missing data that did not allow analysis of associations.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Participants Prior to Randomization | 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) | COWAT | -0.014 beta coefficient |
| All Participants Prior to Randomization | 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) | JLO | -0.003 beta coefficient |
| All Participants Prior to Randomization | 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) | BVMT-R Total | -0.061 beta coefficient |
| All Participants Prior to Randomization | 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) | BVMT-R Delayed | -0.026 beta coefficient |
| All Participants Prior to Randomization | 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) | CVLT-II Total | 0.009 beta coefficient |
| All Participants Prior to Randomization | 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) | PASAT-2 Total | -0.022 beta coefficient |
| All Participants Prior to Randomization | 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) | PASAT-3 Total | -0.061 beta coefficient |
| All Participants Prior to Randomization | 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) | SDMT | -0.137 beta coefficient |
Primary
Change From Baseline in Performance on the Minimal Assessment of Cognitive Function in MS Battery (MACFIMS)
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.
Time frame: baseline, 3 months
Population: includes participants who had MACFIMS testing at both timepoints (baseline and month 3)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| All Participants Prior to Randomization | Change From Baseline in Performance on the Minimal Assessment of Cognitive Function in MS Battery (MACFIMS) | COWAT | 2.5 score | Standard Deviation 8.23 |
| All Participants Prior to Randomization | Change From Baseline in Performance on the Minimal Assessment of Cognitive Function in MS Battery (MACFIMS) | JLO | 0.28 score | Standard Deviation 2.78 |
| All Participants Prior to Randomization | Change From Baseline in Performance on the Minimal Assessment of Cognitive Function in MS Battery (MACFIMS) | BVMT-R Total | 1.81 score | Standard Deviation 5.04 |
| All Participants Prior to Randomization | Change From Baseline in Performance on the Minimal Assessment of Cognitive Function in MS Battery (MACFIMS) | BVMT-R Delayed | 0.95 score | Standard Deviation 1.99 |
| All Participants Prior to Randomization | Change From Baseline in Performance on the Minimal Assessment of Cognitive Function in MS Battery (MACFIMS) | CVLT-II | 2.84 score | Standard Deviation 9.59 |
| All Participants Prior to Randomization | Change From Baseline in Performance on the Minimal Assessment of Cognitive Function in MS Battery (MACFIMS) | PASAT-2 | 2.27 score | Standard Deviation 6.95 |
| All Participants Prior to Randomization | Change From Baseline in Performance on the Minimal Assessment of Cognitive Function in MS Battery (MACFIMS) | PASAT-3 | 0.61 score | Standard Deviation 7.16 |
| All Participants Prior to Randomization | Change From Baseline in Performance on the Minimal Assessment of Cognitive Function in MS Battery (MACFIMS) | SDMT | 0.16 score | Standard Deviation 6.24 |
| Standard Care PAP Therapy (Group 2) | Change From Baseline in Performance on the Minimal Assessment of Cognitive Function in MS Battery (MACFIMS) | SDMT | 1.03 score | Standard Deviation 6.72 |
| Standard Care PAP Therapy (Group 2) | Change From Baseline in Performance on the Minimal Assessment of Cognitive Function in MS Battery (MACFIMS) | COWAT | 2.69 score | Standard Deviation 8.35 |
| Standard Care PAP Therapy (Group 2) | Change From Baseline in Performance on the Minimal Assessment of Cognitive Function in MS Battery (MACFIMS) | CVLT-II | 4.77 score | Standard Deviation 8.88 |
| Standard Care PAP Therapy (Group 2) | Change From Baseline in Performance on the Minimal Assessment of Cognitive Function in MS Battery (MACFIMS) | JLO | 0.60 score | Standard Deviation 3.39 |
| Standard Care PAP Therapy (Group 2) | Change From Baseline in Performance on the Minimal Assessment of Cognitive Function in MS Battery (MACFIMS) | PASAT-3 | 2.53 score | Standard Deviation 8.33 |
| Standard Care PAP Therapy (Group 2) | Change From Baseline in Performance on the Minimal Assessment of Cognitive Function in MS Battery (MACFIMS) | BVMT-R Total | 1.43 score | Standard Deviation 4.99 |
| Standard Care PAP Therapy (Group 2) | Change From Baseline in Performance on the Minimal Assessment of Cognitive Function in MS Battery (MACFIMS) | PASAT-2 | 2.09 score | Standard Deviation 5.14 |
| Standard Care PAP Therapy (Group 2) | Change From Baseline in Performance on the Minimal Assessment of Cognitive Function in MS Battery (MACFIMS) | BVMT-R Delayed | 0.54 score | Standard Deviation 1.88 |
Other Pre-specified
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
Other Pre-specified
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
Other Pre-specified
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
Other Pre-specified
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