Sleep ApneaEarly Phase 1NCT03675022
Effect of Dupilumab on Sleep Apnea in Patients With Rhinosinusitis
A Early Phase 1 study testing Dupilumab in people with Sleep Apnea and Rhinosinusitis Chronic, run by Brigham and Women's Hospital at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Sleep Apnea, Rhinosinusitis Chronic
- What is being tested?
- Dupilumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 9 participants
- Where
- 1 siteUnited States
- Study dates
- 15 Aug 2018to 1 Jul 2022
- Phase
- Early Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 11Show fewer
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
Brigham and Women's Hospital
Boston, Massachusetts, 02115
About this study
Official title: Effect of Dupilumab on Sleep Apnea Severity in Patients With Chronic Rhinosinusitis
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.
Read the 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.
- Conditions
- Sleep Apnea, Rhinosinusitis Chronic
- Being tested
- Dupilumab
- Medical subject headings
- Sleep Apnea Syndromes
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DupilumabDrug
Also called Dupixent
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).
| Study group | Role | What they receive |
|---|---|---|
| Dupilumab | Experimental | Dupilumab injections every 2 weeks. Receives: Drug: Dupilumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percent change in apnea-hypopnea index (AHI) after 16 weeks of dupilumab therapy
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.
Measured: 16 weeks
Secondary outcomes (10)
Effect of 16 weeks of dupilumab on sleep architecture total sleep time
Sleep architecture variables as measured with in-laboratory sleep study of total sleep time
Measured: 16 weeks
Effect of 16 weeks of dupilumab on sleep architecture sleep stage percentages
Sleep architecture variables as measured with in-laboratory sleep study of sleep stage percentages
Measured: 16 weeks
Effect of 16 weeks of dupilumab on sleep architecture arousal index
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.
Measured: 16 weeks
Effect of 16 weeks of dupilumab on sleep architecture oxygen saturation
Sleep architecture variables as measured with in-laboratory sleep study of oxygen saturation
Measured: 16 weeks
Epworth Sleepiness Score (ESS)
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.
Measured: 16 weeks
Pittsburgh Sleep Quality Index (PSQI)
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.
Measured: 16 weeks
Functional Outcomes of Sleep Quality (FOSQ)
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.
Measured: 16 weeks
Subjective sleep quality [visual analog scale(VAS)]
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
Measured: 16 weeks
Effect of 16 weeks of dupilumab on nasal resistance with catheter
Effect of 16 weeks of dupilumab on awake nasal resistance measurements using a pressure catheter
Measured: 16 weeks
Effect of 16 weeks of dupilumab on nasal resistance with mask
Effect of 16 weeks of dupilumab on awake nasal resistance measurements using a mask with pneumotach
Measured: 16 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Sep 2018
- Study start15 Aug 2018
- Primary completion1 Jul 2022
- Study completion1 Jul 2022
Why it stopped: Inability to recruit during COVID
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Sleep ApneaStudies of the same condition, open and under way.
- More trials run by Brigham and Women's HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Early Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 9 participants (actual)
Sponsor and investigators
- Lead sponsor
- Brigham and Women's Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Tanya Laidlaw, MD, Brigham and Women's Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03675022
- Sponsor's protocol ID
- 2018P001031
- Status last verified
- Oct 2022
- First submitted
- 18 Jul 2018
- Last updated
- 5 Oct 2022
- Results posted
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 5 Oct 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Dupilumab on Sleep Apnea Severity in Patients With Chronic Rhinosinusitis
- ClinicalTrials.gov ID
- NCT03675022
- Acronym / sponsor ID
- 2018P001031
- Conditions
- Sleep Apnea, Rhinosinusitis Chronic
- Phase
- Early Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Inability to recruit during COVID
- Enrolment
- 9 participants (actual)
- Lead sponsor
- Brigham and Women's HospitalUniversity, hospital or other
- Study start
- 15 Aug 2018 (actual)
- Primary completion
- 1 Jul 2022 (actual)
- Study completion
- 1 Jul 2022 (actual)
- First posted
- 18 Sep 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Dupilumab | Experimental | Drug: DupilumabDupilumab injections every 2 weeks. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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.
Key exclusion criteria (11 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DupilumabAlso: DupixentThe investigational drug is dupilumab, 300mg in 2ml solution for subcutaneous application. All Patients will receive dupilumab, 300mg, every two weeks (8 subcutaneous injections total). | Drug | Dupilumab |
Primary outcome
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.
10 secondary outcomes
Effect of 16 weeks of dupilumab on sleep architecture total sleep time
Time frame: 16 weeks
Effect of 16 weeks of dupilumab on sleep architecture sleep stage percentages
Time frame: 16 weeks
Effect of 16 weeks of dupilumab on sleep architecture arousal index
Time frame: 16 weeks
Effect of 16 weeks of dupilumab on sleep architecture oxygen saturation
Time frame: 16 weeks
Epworth Sleepiness Score (ESS)
Time frame: 16 weeks
Pittsburgh Sleep Quality Index (PSQI)
Time frame: 16 weeks
Functional Outcomes of Sleep Quality (FOSQ)
Time frame: 16 weeks
Subjective sleep quality [visual analog scale(VAS)]
Time frame: 16 weeks
Effect of 16 weeks of dupilumab on nasal resistance with catheter
Time frame: 16 weeks
Effect of 16 weeks of dupilumab on nasal resistance with mask
Time frame: 16 weeks
Results and safety
The study was stopped early (reason given: Inability to recruit during COVID). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Oct 2022.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Early Phase 1 study testing Dupilumab in people with Sleep Apnea and Rhinosinusitis Chronic, run by Brigham and Women's Hospital at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 5 Oct 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: Inability to recruit during COVID). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percent change in apnea-hypopnea index (AHI) after 16 weeks of dupilumab therapy (time frame: 16 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Oct 2022.