Obstructive Sleep Apnea, OSA, Sleep Apnea
Conditions
Keywords
Obstructive Sleep Apnea, OSA, sleep apnea, snoring, dimethyl fumarate, CPAP, continuous positive airway pressure
Brief summary
The overall purpose of this study is to determine whether the oral medication dimethyl fumarate is an effective treatment for obstructive sleep apnea in patients who are unable, unwilling, or uneager to use positive airway pressure therapy.
Detailed description
Obstructive sleep apnea (OSA) is a common disorder that involves collapse of the upper airway during sleep, leading to low blood oxygen levels and sleep disruption. Untreated OSA increases the risk of many health consequences, including high blood pressure, heart disease, stroke, diabetes, memory problems, fatigue, sleepiness, and impaired memory. Despite its profound public health and societal impact, there are no known medications that can effectively treat OSA, and up to 50% of patients cannot tolerate current treatments. The primary treatment for OSA, known as Continuous Positive Airway Pressure (CPAP), is delivered by a mechanical device and mask that blows air into the airway to keep it open during sleep. Although CPAP controls OSA, many patients can't tolerate the discomfort of the mask, and up to 50% of patients cannot use CPAP appropriately. Several recent studies of OSA patients suggest that inflammation in the airway and the bloodstream may worsen OSA, and that medications that control inflammation may improve OSA. In particular, a previous study from the researchers suggests that multiple sclerosis (MS) patients who are on MS therapies that control inflammation may have less severe OSA than those who are not. MS is an autoimmune disease that is associated with inflammation of the nervous system. As OSA may also be caused or worsened by inflammation, this clinical trial aims to study the effects of a specific MS medication known as dimethyl fumarate (brand name - Tecfidera®) to see if it may also be useful to treat OSA. Tecfidera® is already approved by the Food and Drug Administration (FDA) to treat patients with MS. However, it is not approved by the FDA for the treatment of OSA and is thus considered an investigational drug in this study. Study-related activities will last for 5 months. Consenting participants will receive a baseline overnight sleep study to assess their current sleep apnea severity. Participants will then be given either oral dimethyl fumarate or placebo for a period of 4 months, and will be followed on a monthly basis during the course of the study. At the end of the study, participants will undergo a repeat overnight sleep study to monitor for changes in their sleep apnea severity. Treatments will be assigned at random (like flipping a coin), and participants will not be aware of which treatment they receive. There is a 2/3 chance that participants will receive dimethyl fumarate. Participants will also undergo blood draws and complete several surveys during their monthly study visits. Participants will be compensated for their travel and time throughout the course of the study.
Interventions
DRUGDimethyl fumarate
Dimethyl fumarate capsules will be dispensed during routine study appointments. 120 mg tablets will be dispensed to facilitate dose titrations. Drug will be dispensed in 1 month supply, so that compliance can be reconciled at monthly follow-up visits, and recorded in accountability logs. Participants will be instructed to take the medication with food, in the morning and at dinnertime. If participants miss a dose, they will be instructed to resume their normal dose at the next scheduled time, and be instructed not to take an extra dose at their next dosing interval if they previously miss a dose.
DRUGPlacebo
Placebo capsules will be dispensed during routine study appointments. Placebo will be dispensed in 1 month supply, so that compliance can be reconciled at monthly follow-up visits, and recorded in accountability logs. Participants will be instructed to take the placebo with food, in the morning and at dinnertime. If participants miss a dose, they will be instructed to resume their normal dose at the next scheduled time, and be instructed not to take an extra dose at their next dosing interval if they previously miss a dose.
Sponsors
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Age of 18-65 years at screening; 2. Diagnosis of OSA as confirmed by previous clinical sleep study (polysomnography, PSG); 3. Refusal, inability, or high reluctance to use CPAP regularly for treatment of OSA, despite medical advice; 4. Willingness to undergo repeat sleep study (PSG) and blood studies; 5. Normal immune cell counts, as evidenced by complete blood count (CBC) done at screening
Exclusion criteria
1. Regular use of CPAP within the last 2 months 2. Physical, psychiatric or cognitive impairment that prevents informed consent, PSG, or reliable follow-up; 3. Cardiac conditions that may increase sleep apnea severity (e.g., congestive heart failure or recent heart attack); 4. Current successful treatment for obstructive or central sleep apnea, for example by CPAP, and patient agreement to continue with that treatment; 5. History of surgical treatment for OSA within past 6 months, or subsequent to last PSG confirmation that OSA is present; 6. Active nervous system diseases that may predispose subjects to OSA; 7. Systemic autoimmune disease that could increase inflammation and influence apnea severity (such as rheumatoid arthritis or lupus); 8. Pregnancy or breastfeeding; 9. Use of immunotherapies or immunosuppressants, currently or within past 6 months; 10. Anticipated initiation or dose change in tricyclic antidepressants, selective serotonin uptake inhibitors, or related compounds; 11. Participants with a history of active, serious or persistent infections. 12. Participants with recent surgery (within 3 months prior to screening), or anticipated surgery during the length of the study. 13. Systemic steroid use within the last 2 months (does not include local steroid injections or intranasal steroid spray); 14. Current diagnosis of cancer that is not considered to be cured or in remission by the treating physician, cancer treatment of any kind within the last 6 months prior to screening (chemo, radiation, surgery), or anticipated cancer treatment during the length of the study; 15. History of a lymphoproliferative disorder (such as leukemia); 16. History of Multiple Myeloma 17. History of decreased immune cell counts per a blood test known as a CBC, specifically lymphocyte counts less than 1.2 K/μL at screening. 18. Refusal to use at least one reliable method of birth control (for women of childbearing age) 19. Newly diagnosed (within 2 months) OSA subjects who have an AHI \> 30 and history of serious, recent, or unstable cardiovascular disease (including but not limited to recent MI, recent stroke/TIA, or unstable angina) 20. Participants who report previous motor vehicle accidents or near-misses presumed to be due to excessive sleepiness while driving. 21. 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 |
|---|---|---|
| Mean Change in Apnea Severity as Measured by the Respiratory Disturbance Index (RDI) | Month 0 to Month 4 | For the 50 participants who had interpretable month 4 polysomnography (PSG) data available, mean change in sleep apnea severity, as measured by the mean change in respiratory disturbance index (RDI) between baseline (Month 0) PSG and Month 4 PSG, was calculated. The RDI represents the total number of apneas, hypopneas and respiratory-related arousals per hour of sleep. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Serum Cytokine Levels (Mean Difference of Log-transformed Values) | Month 0 to Month 4 | Levels of markers in the blood known as cytokines (measured in picograms per milliliter) were measured on a monthly basis from Month 0 (baseline) to Month 4. The outcome is the mean difference in cytokine level from baseline to month 4 (mean level at Month 4 - mean level at Baseline). Values were log-transformed for normality, prior to analysis. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dimethyl Fumarate (Tecfidera®) Capsules The starting dose for dimethyl fumarate was 120 mg twice a day orally. After 7 days, the dose was increased to the maintenance dose of 240 mg twice a day. Slower dose escalations were allowed to increase tolerability, if necessary. Participants randomized to dimethyl fumarate were instructed to take this medication twice a day with breakfast and dinner for a period of 4 months.
Dimethyl fumarate: Dimethyl fumarate capsules were dispensed at routine study appointments. 120 mg tablets were dispensed to facilitate dose titrations. Drug was dispensed in 1 month supply, so that compliance could be reconciled at follow-up visits, and recorded in accountability logs. Participants were instructed to take medication with food, (morning and at dinnertime). If participants missed a dose, they were instructed to resume their normal dose at the next scheduled time, and not to take an extra dose at their next dosing interval if they previously miss a dose. | 44 |
| Placebo The placebo is an inert product that looks like a pill and is identical to dimethyl fumarate capsules, but it contains no medicine. Participants randomized to placebo were instructed to take placebo twice a day with breakfast and dinner for a period of 4 months.
Placebo: Placebo capsules were dispensed during routine study appointments. Placebo were dispensed in 1 month supply, so that compliance could be reconciled at monthly follow-up visits, and recorded in accountability logs. Participants were instructed to take the placebo with food, in the morning and at dinnertime. If participants missed a dose, they were instructed to resume their normal dose at the next scheduled time, and not to take an extra dose at their next dosing interval if they previously missed a dose. | 21 |
| Total | 65 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Lost to Follow-up | 3 | 2 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 3 |
Baseline characteristics
| Characteristic | Placebo | Total | Dimethyl Fumarate (Tecfidera®) Capsules |
|---|---|---|---|
| Age, Continuous | 52.5 years STANDARD_DEVIATION 12.4 | 50.2 years STANDARD_DEVIATION 12 | 49.1 years STANDARD_DEVIATION 11.7 |
| Baseline cytokine levels (log-transformed values) Interleukin-10 | 0.392 pg/ml STANDARD_DEVIATION 0.294 | 0.530 pg/ml STANDARD_DEVIATION 0.496 | 0.596 pg/ml STANDARD_DEVIATION 0.558 |
| Baseline cytokine levels (log-transformed values) Interleukin-6 | 0.300 pg/ml STANDARD_DEVIATION 0.249 | 0.372 pg/ml STANDARD_DEVIATION 0.325 | 0.406 pg/ml STANDARD_DEVIATION 0.354 |
| Baseline cytokine levels (log-transformed values) Monocyte Chemoattractant Protein-1 | 2.593 pg/ml STANDARD_DEVIATION 0.21 | 2.619 pg/ml STANDARD_DEVIATION 0.153 | 2.632 pg/ml STANDARD_DEVIATION 0.118 |
| Baseline cytokine levels (log-transformed values) Tissue Necrosis Factor-alpha | 1.009 pg/ml STANDARD_DEVIATION 0.354 | 0.957 pg/ml STANDARD_DEVIATION 0.257 | 0.933 pg/ml STANDARD_DEVIATION 0.195 |
| Region of Enrollment United States | 21 participants | 65 participants | 44 participants |
| Respiratory Disturbance Index (RDI) | 29.0 respiratory events/hour STANDARD_DEVIATION 16.9 | 34 respiratory events/hour STANDARD_DEVIATION 25.1 | 36.4 respiratory events/hour STANDARD_DEVIATION 28 |
| Sex: Female, Male Female | 9 Participants | 33 Participants | 24 Participants |
| Sex: Female, Male Male | 12 Participants | 32 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 44 | 0 / 21 |
| other Total, other adverse events | 27 / 44 | 7 / 21 |
| serious Total, serious adverse events | 1 / 44 | 1 / 21 |
Outcome results
Primary
Mean Change in Apnea Severity as Measured by the Respiratory Disturbance Index (RDI)
For the 50 participants who had interpretable month 4 polysomnography (PSG) data available, mean change in sleep apnea severity, as measured by the mean change in respiratory disturbance index (RDI) between baseline (Month 0) PSG and Month 4 PSG, was calculated. The RDI represents the total number of apneas, hypopneas and respiratory-related arousals per hour of sleep.
Time frame: Month 0 to Month 4
Population: 65 participants were randomized. 14 participants withdrew from the study or were lost to followup. 51 completed study activities. 50 (35 DMF and 15 placebo) both completed the study and had an interpretable Month 4 PSG. One participant's Month 4 PSG was uninterpretable, thus the RDI from this participant could not be included in the final analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dimethyl Fumarate (Tecfidera®) Capsules | Mean Change in Apnea Severity as Measured by the Respiratory Disturbance Index (RDI) | -3.11 respiratory events/hour | Standard Deviation 12.9 |
| Placebo | Mean Change in Apnea Severity as Measured by the Respiratory Disturbance Index (RDI) | 10.2 respiratory events/hour | Standard Deviation 13.1 |
Comparison: Multiple linear regression models were used to calculate treatment effect (DMF or placebo) on mean RDI change, controlling for change in age, gender, BMI, time spent in supine sleep, and time spent in REM sleep.p-value: 0.0124Regression, Linear
Secondary
Mean Change in Serum Cytokine Levels (Mean Difference of Log-transformed Values)
Levels of markers in the blood known as cytokines (measured in picograms per milliliter) were measured on a monthly basis from Month 0 (baseline) to Month 4. The outcome is the mean difference in cytokine level from baseline to month 4 (mean level at Month 4 - mean level at Baseline). Values were log-transformed for normality, prior to analysis.
Time frame: Month 0 to Month 4
Population: Cytokine analyses were conducted for those participants who completed the study and had interpretable Month 4 PSG results. Among this group, 3 participants did not have usable Month 4 blood specimens for this analysis. Thus, the mean difference in cytokine levels was calculated for 47 participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dimethyl Fumarate (Tecfidera®) Capsules | Mean Change in Serum Cytokine Levels (Mean Difference of Log-transformed Values) | Interleukin-6 | 0.038 picograms/milliliter (log-transformed) | Standard Deviation 0.249 |
| Dimethyl Fumarate (Tecfidera®) Capsules | Mean Change in Serum Cytokine Levels (Mean Difference of Log-transformed Values) | Tissue necrosis factor-alpha | -0.002 picograms/milliliter (log-transformed) | Standard Deviation 0.171 |
| Dimethyl Fumarate (Tecfidera®) Capsules | Mean Change in Serum Cytokine Levels (Mean Difference of Log-transformed Values) | Interleukin-10 | 0.084 picograms/milliliter (log-transformed) | Standard Deviation 0.253 |
| Dimethyl Fumarate (Tecfidera®) Capsules | Mean Change in Serum Cytokine Levels (Mean Difference of Log-transformed Values) | Monocyte chemoattractant protein-1 | 0.005 picograms/milliliter (log-transformed) | Standard Deviation 0.136 |
| Placebo | Mean Change in Serum Cytokine Levels (Mean Difference of Log-transformed Values) | Monocyte chemoattractant protein-1 | 0.057 picograms/milliliter (log-transformed) | Standard Deviation 0.157 |
| Placebo | Mean Change in Serum Cytokine Levels (Mean Difference of Log-transformed Values) | Interleukin-6 | -0.015 picograms/milliliter (log-transformed) | Standard Deviation 0.096 |
| Placebo | Mean Change in Serum Cytokine Levels (Mean Difference of Log-transformed Values) | Interleukin-10 | -0.036 picograms/milliliter (log-transformed) | Standard Deviation 0.17 |
| Placebo | Mean Change in Serum Cytokine Levels (Mean Difference of Log-transformed Values) | Tissue necrosis factor-alpha | 0.003 picograms/milliliter (log-transformed) | Standard Deviation 0.257 |