Dimethyl Fumarate for Obstructive Sleep Apnea

Obstructive Sleep Apnea Clinical Trial

Official title:

A Randomized Clinical Trial of Dimethyl Fumarate as a Novel Therapeutic Agent for Obstructive Sleep Apnea

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02438137
• Other study ID #: HUM00080121
• Status: Completed
• Phase: N/A
• First received: April 18, 2015
• Last updated: December 27, 2016
• Start date: May 2015
• Est. completion date: May 2016

Study information

• Verified date: December 2016
• Source: University of Michigan
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Michigan Institute for Clinical and Health Research
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 65
• Est. completion date: May 2016
• Est. primary completion date: April 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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. Subjects with a history of active, serious or persistent infections.

12. Subjects 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. Subjects 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.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Apnea
• Obstructive Sleep Apnea
• OSA
• Sleep Apnea
• Sleep Apnea Syndromes
• Sleep Apnea, Obstructive

Intervention

Drug:
• Dimethyl 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. Subjects will be instructed to take the medication with food, in the morning and at dinnertime. If subjects 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.
• Placebo
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. Subjects will be instructed to take the placebo with food, in the morning and at dinnertime. If subjects 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.

Locations

Country	Name	City	State
United States	University of Michigan	Ann Arbor	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
University of Michigan

Country where clinical trial is conducted

United States, 

References & Publications (18)

Aihara K, Oga T, Chihara Y, Harada Y, Tanizawa K, Handa T, Hitomi T, Uno K, Mishima M, Chin K. Analysis of systemic and airway inflammation in obstructive sleep apnea. Sleep Breath. 2013 May;17(2):597-604. doi: 10.1007/s11325-012-0726-y. — View Citation

Aloia MS, Stanchina M, Arnedt JT, Malhotra A, Millman RP. Treatment adherence and outcomes in flexible vs standard continuous positive airway pressure therapy. Chest. 2005 Jun;127(6):2085-93. — View Citation

Braley TJ, Segal BM, Chervin RD. Sleep-disordered breathing in multiple sclerosis. Neurology. 2012 Aug 28;79(9):929-36. doi: 10.1212/WNL.0b013e318266fa9d. — View Citation

Cofta S, Wysocka E, Dziegielewska-Gesiak S, Michalak S, Piorunek T, Batura-Gabryel H, Torlinski L. Plasma selectins in patients with obstructive sleep apnea. Adv Exp Med Biol. 2013;756:113-9. doi: 10.1007/978-94-007-4549-0_15. — View Citation

Gerdes S, Shakery K, Mrowietz U. Dimethylfumarate inhibits nuclear binding of nuclear factor kappaB but not of nuclear factor of activated T cells and CCAAT/enhancer binding protein beta in activated human T cells. Br J Dermatol. 2007 May;156(5):838-42. — View Citation

Htoo AK, Greenberg H, Tongia S, Chen G, Henderson T, Wilson D, Liu SF. Activation of nuclear factor kappaB in obstructive sleep apnea: a pathway leading to systemic inflammation. Sleep Breath. 2006 Mar;10(1):43-50. — View Citation

Meissner M, Valesky EM, Kippenberger S, Kaufmann R. Dimethyl fumarate - only an anti-psoriatic medication? J Dtsch Dermatol Ges. 2012 Nov;10(11):793-801. doi: 10.1111/j.1610-0387.2012.07996.x. Review. English, German. — View Citation

Scannevin RH, Chollate S, Jung MY, Shackett M, Patel H, Bista P, Zeng W, Ryan S, Yamamoto M, Lukashev M, Rhodes KJ. Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway. J Pharmacol Exp Ther. 2012 Apr;341(1):274-84. doi: 10.1124/jpet.111.190132. — View Citation

Stoof TJ, Flier J, Sampat S, Nieboer C, Tensen CP, Boorsma DM. The antipsoriatic drug dimethylfumarate strongly suppresses chemokine production in human keratinocytes and peripheral blood mononuclear cells. Br J Dermatol. 2001 Jun;144(6):1114-20. — View Citation

Tam CS, Wong M, McBain R, Bailey S, Waters KA. Inflammatory measures in children with obstructive sleep apnoea. J Paediatr Child Health. 2006 May;42(5):277-82. — View Citation

Thomas KS, Motivala S, Olmstead R, Irwin MR. Sleep depth and fatigue: role of cellular inflammatory activation. Brain Behav Immun. 2011 Jan;25(1):53-8. doi: 10.1016/j.bbi.2010.07.245. — View Citation

Ursavas A, Karadag M, Rodoplu E, Yilmaztepe A, Oral HB, Gözü RO. Circulating ICAM-1 and VCAM-1 levels in patients with obstructive sleep apnea syndrome. Respiration. 2007;74(5):525-32. — View Citation

Vandermeeren M, Janssens S, Borgers M, Geysen J. Dimethylfumarate is an inhibitor of cytokine-induced E-selectin, VCAM-1, and ICAM-1 expression in human endothelial cells. Biochem Biophys Res Commun. 1997 May 8;234(1):19-23. — View Citation

Vgontzas AN, Bixler EO, Tan TL, Kantner D, Martin LF, Kales A. Obesity without sleep apnea is associated with daytime sleepiness. Arch Intern Med. 1998 Jun 22;158(12):1333-7. — View Citation

Vgontzas AN, Zoumakis E, Lin HM, Bixler EO, Trakada G, Chrousos GP. Marked decrease in sleepiness in patients with sleep apnea by etanercept, a tumor necrosis factor-alpha antagonist. J Clin Endocrinol Metab. 2004 Sep;89(9):4409-13. — View Citation

Wallbrecht K, Drick N, Hund AC, Schön MP. Downregulation of endothelial adhesion molecules by dimethylfumarate, but not monomethylfumarate, and impairment of dynamic lymphocyte-endothelial cell interactions. Exp Dermatol. 2011 Dec;20(12):980-5. doi: 10.1111/j.1600-0625.2011.01376.x. — View Citation

Walsh JA, Duffin KC, Crim J, Clegg DO. Lower frequency of obstructive sleep apnea in spondyloarthritis patients taking TNF-inhibitors. J Clin Sleep Med. 2012 Dec 15;8(6):643-8. doi: 10.5664/jcsm.2254. — View Citation

Wierinckx A, Brevé J, Mercier D, Schultzberg M, Drukarch B, Van Dam AM. Detoxication enzyme inducers modify cytokine production in rat mixed glial cells. J Neuroimmunol. 2005 Sep;166(1-2):132-43. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean change in apnea severity	Sleep apnea severity, as measured by he respiratory disturbance index (RDI), will be compared between the baseline (Month 0) PSG to the Month 4 PSG. The RDI is the total number of apneas, hypopneas and respiratory-related arousals per hour of sleep.	Month 0 to Month 4	No
Secondary	Change in inflammatory blood markers	Levels of inflammatory markers in the blood (known as cytokines and chemokines, measured in picograms per milliliter) will be measured on a monthly basis from Month 0 (baseline) to Month 4.	Month 0 to Month 4	No