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Effect of Dupilumab on Sleep Apnea in Patients With Rhinosinusitis

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ClinicalTrials.gov Identifier: NCT03675022
Recruitment Status : Recruiting
First Posted : September 18, 2018
Last Update Posted : July 11, 2019
Sponsor:
Information provided by (Responsible Party):
Tanya Laidlaw, MD, Brigham and Women's Hospital

Tracking Information
First Submitted Date  ICMJE July 18, 2018
First Posted Date  ICMJE September 18, 2018
Last Update Posted Date July 11, 2019
Actual Study Start Date  ICMJE August 15, 2018
Estimated Primary Completion Date July 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 1, 2018)
Percent change in apnea-hypopnea index (AHI) after 16 weeks of dupilumab therapy [ Time Frame: 16 weeks ]
The effect of dupilumab on OSA severity in patients with nasal obstruction due to chronic rhinosinusitis with or without nasal polyposis (Bilateral CRS). AHI is the amount of respiratory events that a patient has per hours of sleep.
Original Primary Outcome Measures  ICMJE
 (submitted: September 14, 2018)
Percent change in apnea-hypopnea index (AHI) after 16 weeks of dupilumab therapy [ Time Frame: 16 weeks ]
The effect of dupilumab on OSA severity in patients with nasal obstruction due to chronic rhinosinusitis with or without nasal polyposis (Bilateral CRS).
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 1, 2018)
  • Effect of 16 weeks of dupilumab on sleep architecture total sleep time [ Time Frame: 16 weeks ]
    Sleep architecture variables as measured with in-laboratory sleep study of total sleep time
  • Effect of 16 weeks of dupilumab on sleep architecture sleep stage percentages [ Time Frame: 16 weeks ]
    Sleep architecture variables as measured with in-laboratory sleep study of sleep stage percentages
  • Effect of 16 weeks of dupilumab on sleep architecture arousal index [ Time Frame: 16 weeks ]
    Sleep architecture variables as measured with in-laboratory sleep study of arousal index. The arousal index is how many times a subject wakes up per hour during sleep.
  • Effect of 16 weeks of dupilumab on sleep architecture oxygen saturation [ Time Frame: 16 weeks ]
    Sleep architecture variables as measured with in-laboratory sleep study of oxygen saturation
  • Epworth Sleepiness Score (ESS) [ Time Frame: 16 weeks ]
    Epworth Sleepiness Score (ESS) - The ESS asks the respondent to rate on a 4-point scale (0-3) their usual chances of having dozed off or fallen asleep while engaged in eight different activities that differ widely in their somnificity. The total ESS score (the sum of 8 item-scores) gives an estimate of a more general characteristic, the person's 'average sleep propensity' or ASP, across a wide range of activities in their daily lives. Scores range from 0 to 24, 0 being not sleepy at all and 24 being the most sleepy.
  • Pittsburgh Sleep Quality Index (PSQI) [ Time Frame: 16 weeks ]
    Pittsburgh Sleep Quality Index (PSQI) - The Pittsburgh Sleep Quality Index (PSQI) is an effective instrument used to measure the quality and patterns of sleep in adults. It differentiates "poor" from "good" sleep quality by measuring seven areas (components): subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction over the last month. A total score of "5" or greater is indicative of poor sleep quality. If you scored "5" or more it is suggested that you discuss your sleep habits with a healthcare provider. Each item is weighted on a 0-3 interval scale. The global PSQI score is then calculated by totaling the seven component scores, providing an overall score ranging from 0 to 21, where lower scores denote a healthier sleep quality. A higher score indicates that a person generally has difficulty carrying out certain activities because you are too sleepy or tired.
  • Functional Outcomes of Sleep Quality (FOSQ) [ Time Frame: 16 weeks ]
    Functional Outcomes of Sleep Quality (FOSQ) - Disease specific quality of life questionnaire to determine functional status in adults; measures are designed to assess the impact of disorders of excessive sleepiness on multiple activities of everyday living and the extent to which these abilities are improved by effective treatment. This scale has 30 items, 5 factor subscales, scaling of items is 0-4. To obtain total score, take all the subscale scores and calculate the mean of these scores and then multiply that mean by five. The potential range of scores for the total score is 5-20.
  • Subjective sleep quality [visual analog scale(VAS)] [ Time Frame: 16 weeks ]
    Subjective sleep quality [visual analog scale(VAS)] - on a scale of 1-10, subjects answer questions on how sleepy they are with 0 being least sleepy and 10 being most sleepy
  • Effect of 16 weeks of dupilumab on nasal resistance with catheter [ Time Frame: 16 weeks ]
    Effect of 16 weeks of dupilumab on awake nasal resistance measurements using a pressure catheter
  • Effect of 16 weeks of dupilumab on nasal resistance with mask [ Time Frame: 16 weeks ]
    Effect of 16 weeks of dupilumab on awake nasal resistance measurements using a mask with pneumotach
Original Secondary Outcome Measures  ICMJE
 (submitted: September 14, 2018)
  • Effect of 16 weeks of dupilumab on sleep architecture total sleep time [ Time Frame: 16 weeks ]
    Sleep architecture variables as measured with in-laboratory sleep study of total sleep time
  • Effect of 16 weeks of dupilumab on sleep architecture sleep stage percentages [ Time Frame: 16 weeks ]
    Sleep architecture variables as measured with in-laboratory sleep study of sleep stage percentages
  • Effect of 16 weeks of dupilumab on sleep architecture arousal index [ Time Frame: 16 weeks ]
    Sleep architecture variables as measured with in-laboratory sleep study of arousal index
  • Effect of 16 weeks of dupilumab on sleep architecture oxygen saturation [ Time Frame: 16 weeks ]
    Sleep architecture variables as measured with in-laboratory sleep study of oxygen saturation
  • Effect of 16 weeks of dupilumab on subjective sleep quality and quality of life scores [ Time Frame: 16 weeks ]
    Epworth Sleepiness Score (ESS) - The ESS asks the respondent to rate on a 4-point scale (0-3) their usual chances of having dozed off or fallen asleep while engaged in eight different activities that differ widely in their somnificity. The total ESS score (the sum of 8 item-scores) gives an estimate of a more general characteristic, the person's 'average sleep propensity' or ASP, across a wide range of activities in their daily lives. Scores range from 0 to 24, 0 being not sleepy at all and 24 being the most sleepy.
  • Effect of 16 weeks of dupilumab on subjective sleep quality and quality of life scores [ Time Frame: 16 weeks ]
    Pittsburgh Sleep Quality Index (PSQI) - The Pittsburgh Sleep Quality Index (PSQI) is an effective instrument used to measure the quality and patterns of sleep in adults. It differentiates "poor" from "good" sleep quality by measuring seven areas (components): subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction over the last month. A total score of "5" or greater is indicative of poor sleep quality. If you scored "5" or more it is suggested that you discuss your sleep habits with a healthcare provider. Each item is weighted on a 0-3 interval scale. The global PSQI score is then calculated by totaling the seven component scores, providing an overall score ranging from 0 to 21, where lower scores denote a healthier sleep quality. A higher score indicates that a person generally has difficulty carrying out certain activities because you are too sleepy or tired.
  • Effect of 16 weeks of dupilumab on subjective sleep quality and quality of life scores [ Time Frame: 16 weeks ]
    Functional Outcomes of Sleep Quality (FOSQ) - Disease specific quality of life questionnaire to determine functional status in adults; measures are designed to assess the impact of disorders of excessive sleepiness on multiple activities of everyday living and the extent to which these abilities are improved by effective treatment. This scale has 30 items, 5 factor subscales, scaling of items is 0-4. To obtain total score, take all the subscale scores and calculate the mean of these scores and then multiply that mean by five. The potential range of scores for the total score is 5-20.
  • Effect of 16 weeks of dupilumab on subjective sleep quality and quality of life scores [ Time Frame: 16 weeks ]
    Subjective sleep quality [visual analog scale(VAS)] - on a scale of 1-10, subjects answer questions on how sleepy they are with 0 being least sleepy and 10 being most sleepy
  • Effect of 16 weeks of dupilumab on nasal resistance [ Time Frame: 16 weeks ]
    Effect of 16 weeks of dupilumab on awake nasal resistance measurements using a pressure catheter
  • Effect of 16 weeks of dupilumab on nasal resistance [ Time Frame: 16 weeks ]
    Effect of 16 weeks of dupilumab on awake nasal resistance measurements using a mask with pneumotach
Current Other Pre-specified Outcome Measures
 (submitted: October 1, 2018)
  • Sino-Nasal Outcome Test (SNOT-22) [ Time Frame: 16 weeks ]
    Effect of 16 weeks of dupilumab on the 22 item Sino-Nasal Outcome Test (SNOT-22)
  • Visual analog scale (VAS) for rhinosinusitis [ Time Frame: 16 weeks ]
    Effect of 16 weeks of dupilumab on the Visual analog scale (VAS) for rhinosinusitis. - on a scale of 1-10, subjects answer questions on their rhinosinusitis symptom with 0 being least severe and 10 being most severe
  • University of Pennsylvania Smell Identification Test (UPSIT) [ Time Frame: 16 weeks ]
    Effect of 16 weeks of dupilumab on smell identification, using the University of Pennsylvania Smell Identification Test (UPSIT)
  • Effect of 16 weeks of dupilumab on peak nasal inspiratory flow (PNIF) [ Time Frame: 16 weeks ]
    Effect of 16 weeks of dupilumab on peak nasal inspiratory flow (PNIF)
Original Other Pre-specified Outcome Measures
 (submitted: September 14, 2018)
  • Effect of 16 weeks of dupilumab on chronic rhinosinusitis symptoms [ Time Frame: 16 weeks ]
    Effect of 16 weeks of dupilumab on the 22 item Sino-Nasal Outcome Test (SNOT-22)
  • Effect of 16 weeks of dupilumab on chronic rhinosinusitis symptoms [ Time Frame: 16 weeks ]
    Effect of 16 weeks of dupilumab on the Visual analog scale (VAS) for rhinosinusitis. - on a scale of 1-10, subjects answer questions on their rhinosinusitis symptom with 0 being least severe and 10 being most severe
  • Effect of 16 weeks of dupilumab on smell [ Time Frame: 16 weeks ]
    Effect of 16 weeks of dupilumab on smell identification, using the University of Pennsylvania Smell Identification Test (UPSIT)
  • Effect of 16 weeks of dupilumab on peak nasal inspiratory flow (PNIF) [ Time Frame: 16 weeks ]
    Effect of 16 weeks of dupilumab on peak nasal inspiratory flow (PNIF)
 
Descriptive Information
Brief Title  ICMJE Effect of Dupilumab on Sleep Apnea in Patients With Rhinosinusitis
Official Title  ICMJE Effect of Dupilumab on Sleep Apnea Severity in Patients With Chronic Rhinosinusitis
Brief Summary

Obstructive Sleep Apnea (OSA) is a common disorder with serious consequences that remains underrecognized, with >80% of OSA patients undiagnosed, and undertreated due to inadequate treatment options. The development of additional treatments for OSA, such as pharmacotherapy, are critically needed.

The collaboration between Regeneron and Sanofi are funding this project. Regeneron will be providing the drug and the contract will be with Regeneron. Both companies are involved as it is a collaboration across the companies.

Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Early Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Sleep Apnea
  • Rhinosinusitis Chronic
Intervention  ICMJE 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).
Other Name: Dupixent
Study Arms  ICMJE Experimental: Dupilumab
Dupilumab injections every 2 weeks.
Intervention: Drug: Dupilumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 14, 2018)
22
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 2020
Estimated Primary Completion Date July 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Lauren Hess 617-732-8976 lhess1@bwh.harvard.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03675022
Other Study ID Numbers  ICMJE 2018P001031
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Tanya Laidlaw, MD, Brigham and Women's Hospital
Study Sponsor  ICMJE Brigham and Women's Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Brigham and Women's Hospital
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP