Effect of Dupilumab on Sleep Apnea in Patients With Rhinosinusitis
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Mücərrəd
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Clinical Background on OSA OSA is a prevalent disorder, with roughly 1 in 5 adults estimated to have at least mild OSA and 1 in 15 estimated to have at least moderate OSA. Furthermore, OSA causes a number of adverse cardiovascular, neurocognitive, and daytime functional consequences. As a result, understanding the pathophysiology and developing treatments is a major public health goal. Unfortunately, only approximately 50% of patients tolerate the main therapy for OSA, Continuous Positive Airway Pressure (CPAP). Therefore, new therapeutic approaches are clearly needed.
OSA is caused by collapse of the pharyngeal airway during sleep due to the sleep state-related loss of pharyngeal muscle activity. High nasal resistance can contribute to pharyngeal collapse as well by increasing the suction pressure downstream in the velo- and oropharynx. In fact, a recent study in 139 patients with chronic rhinosinusitis (CRS) demonstrated an extremely high prevalence of OSA (65% of the CRS patients had OSA compared to a prevalence in the normal population of 5-15%). Therefore, a drug that reduces nasal congestion and pharyngeal edema, such as dupilumab, could potentially improve OSA in some patients.
Immunologic Background on OSA and role of Type 2 inflammation Indeed, preliminary patient-reported outcomes data from early clinical trials with dupilumab have shown that dupilumab treatment of patients with sinus disease reduces reports of nocturnal awakenings, as well as sleep-related outcomes on the SinoNasal Outcome Test (SNOT-22). In addition to the known effects of dupilumab on the reduction of nasal polyp size/volume, there is ample evidence to propose that the specific anti-inflammatory effects achieved with IL-4Rα blockade will be particularly relevant to a potential therapeutic effect of dupilumab on OSA in patients with comorbid CRS. There are a number of Type 2 inflammatory markers that are increased in patients with CRS and OSA, which taken together suggest that OSA in these patients is truly an inflammatory disease, and not solely a disease of abnormal anatomy. Serum IL-4 levels are elevated in patients with rhinitis and OSA, and those levels are negatively correlated with time spent in REM sleep. Furthermore, two inflammatory markers of mast cell activation, urinary leukotriene E4 and urinary prostaglandin D2, are also known to be elevated in OSA, likely due to the increased chronic mast cell stimulation afforded by the high circulating IL-4 levels. Strikingly, both urinary leukotriene E4 and prostaglandin D2 levels correlate with OSA severity, as measured by either percentage of overnight time spent with SaO2 <90% or the apnea/hypopnea index (AHI).
There is additional clinical evidence to suggest that OSA may be more than "just" an anatomic disease. Although endoscopic sinus surgery to remove inflamed sinus tissue in patients with OSA and CRS does improve OSA symptoms, non-surgical anti-inflammatory treatments, including intranasal steroids and leukotriene modification with montelukast, have also been found to improve OSA symptoms and decrease the AHI.
Given these immunological findings, the investigators suspect that extensive Type 2 inflammation is a major contributing factor for patients with CRS and OSA, and that IL-4Rα blockade will be a powerful therapeutic tool in sleep apnea. In combination with the preliminary patient-reported outcomes data suggesting that dupilumab improves sleep quality, the investigators feel confident that dupilumab will successfully provide a clinically-quantifiable therapeutic improvement on the severity of OSA in patients with CRS and OSA. As there are currently no FDA-approved medications for the treatment of OSA, and 65% of all patients with CRS suffer from OSA, the investigators feel as though positive results from this pilot trial would be a powerful step towards providing a new biologic therapy to an underserved medical population.
Tarixlər
Son Doğrulandı: | 06/30/2019 |
İlk təqdim: | 07/17/2018 |
Təxmini qeydiyyat təqdim edildi: | 09/13/2018 |
İlk Göndərmə: | 09/17/2018 |
Son Yeniləmə Göndərildi: | 07/08/2019 |
Son Yeniləmə Göndərildi: | 07/10/2019 |
Həqiqi Təhsilin Başlama Tarixi: | 08/14/2018 |
Təxmini İlkin Tamamlanma Tarixi: | 06/30/2020 |
Təxmini İşin Tamamlanma Tarixi: | 06/30/2020 |
Vəziyyət və ya xəstəlik
Müdaxilə / müalicə
Drug: Dupilumab
Faza
Qol Qrupları
Qol | Müdaxilə / müalicə |
---|---|
Experimental: Dupilumab Dupilumab injections every 2 weeks. | Drug: Dupilumab The investigational drug is dupilumab, 300mg in 2ml solution for subcutaneous application. All Patients will receive dupilumab, 300mg, every two weeks (8 subcutaneous injections total). |
Uyğunluq Kriteriyaları
Təhsil üçün uyğun yaşlar | 18 Years Üçün 18 Years |
Təhsilə Uyğun Cinslər | All |
Sağlam Könüllüləri qəbul edir | Bəli |
Kriteriyalar | Inclusion Criteria: - Adults (18 to 65 years) - BMI < 35 kg/m2 - Bilateral CRS (clinical diagnosis) with or without nasal polyposis despite intranasal corticosteroid treatment for at least 3 months. - Patients will be required to report at least 2 of the following symptoms prior to screening: (1) nasal obstruction/blockage, (2) nasal discharge or discolored postnasal drainage, (3) facial pain or pressure, and (4) reduction or loss of sense of smell, with symptom duration of at least 3 months. - Suffering from OSA with AHI > 10 episodes/hr based on the home sleep test (described below) and not using CPAP. - Willing, committed, and able to return for all clinic visits and complete all study-related procedures. - In females of childbearing potential: Negative pregnancy test. A urine pregnancy test will be performed in each site visit to ensure that the patients are not pregnant while using dupilumab. Exclusion Criteria: - Concurrent sleep disorder - Previous participation in any clinical trial of dupilumab in which active treatment was administered. - Oral corticosteroids, monoclonal antibodies, immunosuppressive treatment, or anti-immunoglobulin E (anti-IgE) therapy during the 6 weeks preceding the screening. - Concomitant conditions making them not evaluable for the primary endpoint. Prior diagnosis of OSA will not be exclusionary. - Lactating females or pregnant females. - Subjects for whom there is concern about compliance with the protocol procedures. - Any medical condition which, in the opinion of the Investigator, would interfere with participation in the study or place the subject at risk (chronic infectious diseases such as TB, HIV, Hepatitis, etc.). - History of hypersensitivity to the study drug. - History of substance abuse (drug or alcohol) or any other factor (e.g., serious psychiatric condition) that could limit the subject's ability to comply with study procedures. - Subjects must refrain from intranasal decongestants for 1 week prior to starting the study. - Subjects with a medical history of HSV1 or HSV2, or with a history of recurrent conjunctivitis. |
Nəticə
İlkin nəticə tədbirləri
1. Percent change in apnea-hypopnea index (AHI) after 16 weeks of dupilumab therapy [16 weeks]
İkincili Nəticə Tədbirləri
1. Effect of 16 weeks of dupilumab on sleep architecture total sleep time [16 weeks]
2. Effect of 16 weeks of dupilumab on sleep architecture sleep stage percentages [16 weeks]
3. Effect of 16 weeks of dupilumab on sleep architecture arousal index [16 weeks]
4. Effect of 16 weeks of dupilumab on sleep architecture oxygen saturation [16 weeks]
5. Epworth Sleepiness Score (ESS) [16 weeks]
6. Pittsburgh Sleep Quality Index (PSQI) [16 weeks]
7. Functional Outcomes of Sleep Quality (FOSQ) [16 weeks]
8. Subjective sleep quality [visual analog scale(VAS)] [16 weeks]
9. Effect of 16 weeks of dupilumab on nasal resistance with catheter [16 weeks]
10. Effect of 16 weeks of dupilumab on nasal resistance with mask [16 weeks]
Digər nəticə tədbirləri
1. Sino-Nasal Outcome Test (SNOT-22) [16 weeks]
2. Visual analog scale (VAS) for rhinosinusitis [16 weeks]
3. University of Pennsylvania Smell Identification Test (UPSIT) [16 weeks]
4. Effect of 16 weeks of dupilumab on peak nasal inspiratory flow (PNIF) [16 weeks]