Efficacy of Dupilumab for Patients With Chronic Rhinosinusitis Without Nasal Polyps (CRSsNP): a Randomized Double Blind Placebo Controlled Phase II Study

  • STATUS
    Recruiting
  • End date
    Oct 15, 2023
  • participants needed
    50
  • sponsor
    Johns Hopkins University
Updated on 28 October 2022
antibiotic therapy
antibiotics
endoscopy
rhinosinusitis
eosinophil count
dupilumab
nasal polyp

Summary

The overarching objective of this study is to determine the clinical effectiveness of dupilumab for the treatment of CRS that includes several potential disease endotypes with the exclusion of the nasal polyp cluster that has previously been determined. The additional information gained from secondary and exploratory outcomes will help provide important insight for applied research studies and may also provide practical guidance to clinicians on how to select patients for treatment.

Description

Approximately 12% of adults in the United States, United Kingdom and other industrialized nations suffer from chronic sinus disease. Corticosteroids and antibiotic regimens are often used to treat the condition but the level of evidence to justify this approach is limited and at best offers only a transient solution. Furthermore, adverse side effects from the use of long-term oral steroids and concerns about skewing of the mucosal microbiota from overuse of antibiotics make these options problematic.

Currently, there are insufficient options for the approximately 30 million patients in the US suffering from chronic sinus disease. Recent phase 3 clinical trials found that dupilumab, an anti-IL4α receptor monoclonal antibody, reduces symptoms and polyp size in individuals with CRS with nasal polyps (CRSwNP). Similarly anti-IL5 antibodies have also been shown to have modest efficacy in this group of patients. However, for the approximately 65% of individuals with non-polyp related chronic sinus disease, these agents were not evaluated and there remains few viable options for therapy.

Chronic rhinosinusitis is defined as symptoms of nasal obstruction, facial pain or pressure, and mucopurulent drainage for at least 12 weeks along with evidence of mucosal disease by radiographic evidence or rhinoscopy. At least ten endotypes have been described although there is considerable overlap in terms of mucosal morphology, allergic status, the presence of polypoid tissue, and expression of biomarkers such as cytokines, specific IgE and other proteins. It may be incorrect to assume that the effectiveness of dupilumab demonstrated for those suffering with nasal polyps is exclusive to this CRS cluster alone.

One aspect to explain the differential effects of certain drugs and biologics on the treatment of CRS relates to host nasal and sinus microbial environment. The microbiome of CRS patients has been found to have reduced diversity, increased bacterial populations, and ultimately to have less stable bacterial networks. This imbalance of the microbiome may be a potential cause for sinus inflammation. Studies have demonstrated that Propionibacterium acnes for example, acts as an important stabilizing organism in the bacterial networks. Removal of this bacterial species e.g. from antibiotic use, may allow for more pathogenic organisms such as Staphylococcus or Streptococcus to flourish leading to increased inflammation.

An example of how Staphylococcus aureus may increase inflammation is through the production of superantigen that is thought to skew nasal inflammatory responses towards a Th2 dominated disease endotype. Other groups, have concluded that the host mucosal microbiota helps predict disease severity and might also predict susceptibility to certain therapies. Indeed, treatment with certain antibiotics has shown to modulate mucosal bacterial populations leading to clinical improvement and reduced polyp formation in some patients. It is not known whether host microbial and inflammatory milieu adequately predicts polyp formation or helps predict treatment success in the presence of dupilumab. The current study will include investigation of this important exploratory outcome.

The investigators have previously shown that modulation of both the innate and adaptive immune responses can impact dendritic cell and basophil responses in vitro and that these changes correlate with treatment success of patients with chronic allergic rhinosinusitis. The investigators also more recently discovered that IL-4 and IL-13 secreted by human basophils upregulates CD20 (mannose receptor), CD23 (FcεRII) and pSTAT6 expression on monocytes, while also promoting CCL17 (TARC) production by these cells. Other investigators have shown that the mannose receptor on monocytes negatively modulates TLR-4 innate immune signaling on dendritic cells that in turn affects T-cell polarization and response to allergens. The investigators might expect dupilumab to help attenuate this pathway resulting in a reduction of local sIgE production in the mucosa for example. It is already known that dupilumab reduces the expression of other inflammatory mediators such as CCL17 in asthma and atopic dermatitis. These aspects will be examined in the exploratory investigations using cell culture assays, flow cytometry and immunofluorescence pre and post treatment.

The overarching objective of this study is to determine the clinical effectiveness of dupilumab for the treatment of CRS that includes several potential disease endotypes with the exclusion of the nasal polyp cluster that has previously been determined. The additional information gained from secondary and exploratory outcomes will help provide important insight for applied research studies and may also provide practical guidance to clinicians on how to select patients for treatment.

Details
Condition Chronic Sinusitis
Treatment Placebo, Dupilumab
Clinical Study IdentifierNCT04362501
SponsorJohns Hopkins University
Last Modified on28 October 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Age 18-75 with history of chronic sinusitis without polyps
SNOT-22 score of at least 30 at baseline
Bilateral Lund-Mackay CT score 4 or more and/or MLK endoscopy score 4 or more
Blood eosinophil count of at least 300/ul and/or SPT positive to at least 5/30 allergens, or eosinophil less than 300/ul and SPT negative (Th2 low group)
Prior oral steroid or antibiotic use is acceptable but not required for entry
Informed Consent
Effective birth control (with <1% failure rate), post menopausal or documented abstinence
Women ≥50 years old would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatment
All male subjects who are sexually active must agree to use an acceptable method of contraception (condom or vasectomy) from V1-V16

Exclusion Criteria

Immunosuppression other than oral steroids in the past 3 months
History of nasal polyps within the past 3 years or noted at screening by CT or endoscopy
Acute sinusitis at the time of entry
Acute fungal sinusitis at the time of entry
Uncontrolled asthma
Cystic fibrosis
Primary immune deficiency including CVID
Other; serious concomitant illness or sinus disease that the investigator determines to disqualify
A history of known immunodeficiency disorder including HIV
History of hepatitis B or C
Primary ciliary dyskinesia (PCD)
Use of any biologic medication within the last 5 months or 5 half-lives whichever is longer
Receipt of any investigational non-biologic within 5 half-lives prior to visit 0
Receipt of immunoglobulin or blood products within 30 days prior to V1
Scheduled sinus surgery
Significant structural abnormalities or severe septal deviation
Symptomatic or untreated life threatening cardiopulmonary disorders
History of cancer not in remission at least 5 years prior to the date informed consent
Subjects who are febrile (≥38°C; ≥100.4°F)
Untreated helminth parasitic infection within 24 weeks prior to informed consent
Pregnant or nursing
Any other medical illness that precludes study involvement
History of anaphylaxis to any biologic therapy or vaccine
The following medications are excluded
Any type of anti-interleukin therapy (e.g. Omalizumab, benralizumab, dupilumab mepolizumab, reslizumab, lebrikizumab etc.) within the last 5 months or 5 half-lives whichever is longer
Receipt of any investigational non-biologic within 30 days or 5 half-lives prior to visit 0, whichever is longer
Immunosuppressive medications such as methotrexate, azathioprine, cyclosporine, tacrolimus
Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent is obtained
Daily high dose aspirin greater than 81mg daily
Allergen Immunotherapy during build-up phase during the last three months
Other medications that could interfere with the action of dupilumab or suppress eosinophils
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