Dimethyl Fumarate for Obstructive Sleep Apnea

NCT02438137 | Completed Phase 2 Results FDA Drug

• 1 other identifier: HUM00080121
• Study Type: interventional
• Target: 65
• Locations: 1 country
• Sites: 1

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.

Conditions

Obstructive Sleep Apnea; OSA; Sleep Apnea

Keywords

Obstructive Sleep Apnea; OSA; sleep apnea; snoring; dimethyl fumarate; CPAP; continuous positive airway pressure

Outcome Measures

Primary Outcomes (1)

• 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.

  Month 0 to Month 4

Secondary Outcomes (1)

• Mean Change in Serum Cytokine Levels (Mean Difference of Log-transformed Values)

  Month 0 to Month 4

Study Arms (2)

Dimethyl Fumarate (Tecfidera®) capsules

ACTIVE COMPARATOR

The starting dose for dimethyl fumarate (Tecfidera®, http://www.tecfidera.com/pdfs/full-prescribing-information.pdf) is 120 mg twice a day orally. After 7 days, the dose should be increased to the maintenance dose of 240 mg twice a day, though slower dose escalations are possible to increase tolerability, if necessary. Participants randomized to dimethyl fumarate will be instructed to take this medication twice a day with breakfast and dinner for a period of 4 months.

Drug: Dimethyl fumarate

Placebo

PLACEBO COMPARATOR

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 will be instructed to take placebo twice a day with breakfast and dinner for a period of 4 months.

Drug: Placebo

Interventions

Dimethyl fumarate DRUG

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.

Also known as: Tecfidera

Dimethyl Fumarate (Tecfidera®) capsules

Placebo DRUG

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.

Placebo

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age of 18-65 years at screening;
• Diagnosis of OSA as confirmed by previous clinical sleep study (polysomnography, PSG);
• Refusal, inability, or high reluctance to use CPAP regularly for treatment of OSA, despite medical advice;
• Willingness to undergo repeat sleep study (PSG) and blood studies;
• Normal immune cell counts, as evidenced by complete blood count (CBC) done at screening

You may not qualify if:

• Regular use of CPAP within the last 2 months
• Physical, psychiatric or cognitive impairment that prevents informed consent, PSG, or reliable follow-up;
• Cardiac conditions that may increase sleep apnea severity (e.g., congestive heart failure or recent heart attack);
• Current successful treatment for obstructive or central sleep apnea, for example by CPAP, and patient agreement to continue with that treatment;
• History of surgical treatment for OSA within past 6 months, or subsequent to last PSG confirmation that OSA is present;
• Active nervous system diseases that may predispose subjects to OSA;
• Systemic autoimmune disease that could increase inflammation and influence apnea severity (such as rheumatoid arthritis or lupus);
• Pregnancy or breastfeeding;
• Use of immunotherapies or immunosuppressants, currently or within past 6 months;
• Anticipated initiation or dose change in tricyclic antidepressants, selective serotonin uptake inhibitors, or related compounds;
• Participants with a history of active, serious or persistent infections.
• Participants with recent surgery (within 3 months prior to screening), or anticipated surgery during the length of the study.
• Systemic steroid use within the last 2 months (does not include local steroid injections or intranasal steroid spray);
• 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;
• History of a lymphoproliferative disorder (such as leukemia);

Sponsors & Collaborators

• University of Michigan: lead

Study Sites (1)

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Related Publications (19)

• 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. doi: 10.1378/chest.127.6.2085.

  PMID: 15947324 BACKGROUND

• 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. doi: 10.1001/archinte.158.12.1333.

  PMID: 9645828 BACKGROUND

• 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. doi: 10.1210/jc.2003-031929.

  PMID: 15356039 BACKGROUND

• 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. Epub 2010 Jul 23.

  PMID: 20656013 BACKGROUND

• 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. Epub 2012 Jun 7.

  PMID: 22674397 BACKGROUND

• 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. doi: 10.1111/j.1440-1754.2006.00854.x.

  PMID: 16712558 BACKGROUND

• Ursavas A, Karadag M, Rodoplu E, Yilmaztepe A, Oral HB, Gozu RO. Circulating ICAM-1 and VCAM-1 levels in patients with obstructive sleep apnea syndrome. Respiration. 2007;74(5):525-32. doi: 10.1159/000097770. Epub 2006 Dec 4.

  PMID: 17148932 BACKGROUND

• 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.

  PMID: 22836626 BACKGROUND

• 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. doi: 10.1007/s11325-005-0046-6.

  PMID: 16491391 BACKGROUND

• 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.

  PMID: 23243397 BACKGROUND

• 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. Epub 2012 Aug 15.

  PMID: 22895593 BACKGROUND

• 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. doi: 10.1111/j.1365-2133.2007.07779.x. Epub 2007 Mar 23.

  PMID: 17381463 BACKGROUND

• 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. doi: 10.1046/j.1365-2133.2001.04220.x.

  PMID: 11422029 BACKGROUND

• Wierinckx A, Breve 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. doi: 10.1016/j.jneuroim.2005.05.013.

  PMID: 15993952 BACKGROUND

• 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. doi: 10.1006/bbrc.1997.6570.

  PMID: 9168952 BACKGROUND

• Wallbrecht K, Drick N, Hund AC, Schon 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. Epub 2011 Oct 13.

  PMID: 21995308 BACKGROUND

• 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. Epub 2012 Aug 17. English, German.

  PMID: 22897153 BACKGROUND

• 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. Epub 2012 Jan 20.

  PMID: 22267202 BACKGROUND

• Braley TJ, Huber AK, Segal BM, Kaplish N, Saban R, Washnock-Schmid JM, Chervin RD. A randomized, subject and rater-blinded, placebo-controlled trial of dimethyl fumarate for obstructive sleep apnea. Sleep. 2018 Aug 1;41(8). doi: 10.1093/sleep/zsy109.

  PMID: 29800466 DERIVED

MeSH Terms

Conditions

Sleep Apnea, Obstructive; Sleep Apnea Syndromes; Snoring

Interventions

Dimethyl Fumarate

Condition Hierarchy (Ancestors)

Apnea; Respiration Disorders; Respiratory Tract Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Nervous System Diseases; Respiratory Sounds; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Fumarates; Dicarboxylic Acids; Acids, Acyclic; Carboxylic Acids; Organic Chemicals

Results Point of Contact

• Title: Tiffany Braley, M.D., M.S.
• Organization: UMichigan

tbraley@med.umich.edu

734-232-1147

Study Officials

• Tiffany J. Braley, MD, MS

  University of Michigan

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor, Department of Neurology

Study Record Dates

• First Submitted: April 18, 2015
• First Posted: May 8, 2015
• Study Start: May 1, 2015
• Primary Completion: April 1, 2016
• Study Completion: May 1, 2016
• Last Updated: May 31, 2017
• Results First Posted: May 31, 2017

Record last verified: 2017-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)