Efficacy of Dupilumab for Patients With Chronic Rhinosinusitis Without Nasal Polyps (CRSsNP)

• ClinicalTrials.gov Identifier: NCT04362501
• Recruitment Status: Recruiting
• First Posted: April 27, 2020
• Last Update Posted: October 13, 2022
• Sponsor: Johns Hopkins University
• Information provided by (Responsible Party): Johns Hopkins University

Tracking Information

• First Submitted Date: April 21, 2020
• First Posted Date: April 27, 2020
• Last Update Posted Date: October 13, 2022
• Actual Study Start Date: October 15, 2020
• Estimated Primary Completion Date: October 15, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 24, 2020)

SNOT-22 [ Time Frame: Every two weeks for six months ]

Sino-Nasal Outcome Test (SNOT-22) survey score after six months treatment (range 0-110). Higher score means worse symptoms.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 24, 2020)

• Mini-RQLQ [ Time Frame: Every two weeks for six months ]
  Mini-RQLQ (Rhinoconjunctivitis Quality of Life) validated survey (0-84). Higher score means worse symptoms.
• UPSIT [ Time Frame: Every two weeks for six months ]
  University of Pennsylvania Smell Identification Test (UPSIT) smell test (0-40). Higher score means better sense of smell.
• Rescue medication [ Time Frame: Every two weeks for six months ]
  Rescue medication use of corticosteroids. Specifically, prednisone mg use total over six month period.
• CT Score [ Time Frame: Once at screening and then at six month final visit ]
  Sinus CT Lund-Mackay (LM) score (0-24). Higher score means larger polyps.
• Rhinoscopy Score [ Time Frame: Once at screening and then at six month final visit ]
  Rhinoscopy modified Lund-Kennedy (MLK) score (0-12). Higher score means worse sinus disease.
• Drop out rate rate [ Time Frame: Continuous during entire length of study which is three years. ]
  Number of patients who leave the study. Individual participants will be considered to have dropped out if they leave the study for any reason during the six month treatment period. A total count will be collected over the entire study length estimated to be three years. This number will be divided by the total enrollment number to determine the rate of drop out.
• Adverse event rate [ Time Frame: Continuous during entire length of study which is three years. ]
  Significant Adverse Reactions (SAE). Individual participants will be monitored for serious adverse events during the six month treatment period. A total count will be collected over the entire study length estimated to be three years. This number will be divided by the total enrollment number to determine the rate of adverse events.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

Detailed 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.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

double blind randomized placebo controlled

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment

• Condition: Chronic Sinusitis

Intervention

• Biological: dupilumab
  300mg dupixent SC every two weeks for six months
  Other Name: Dupixent
• Drug: placebo
  placebo SC injection every two weeks for six months

Study Arms

• Experimental: dupilumab treatment group
  dupilumab treatment group
  Intervention: Biological: dupilumab
• Placebo Comparator: placebo group
  placebo group
  Intervention: Drug: placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 24, 2020): 50
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 15, 2023
• Estimated Primary Completion Date: October 15, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Jeanne Hoddinott; 4105508017; hoddin1@jhmi.edu

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04362501
• Other Study ID Numbers: IRB00229130
• Has Data Monitoring Committee: No

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

• Plan to Share IPD: No

• Current Responsible Party: Johns Hopkins University
• Original Responsible Party: Same as current
• Current Study Sponsor: Johns Hopkins University
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Jody Tversky; Johns Hopkins University

• PRS Account: Johns Hopkins University
• Verification Date: October 2022