Clinical trial NCT03450083: Benralizumab Effect on Severe Chronic Rhinosinusitis With Eosinophilic Polyposis
Official title: Benralizumab Effect on Severe Chronic Rhinosinusitis With Eosinophilic Polyposis: A Phase II Randomized Placebo Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Rhinosinusitis (Diagnosis)
Nasal Polyps
Eosinophilia
Lead sponsor: Johns Hopkins University
Sponsor class: OTHER
First posted: 2018-03-01
Enrollment: 33
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Benralizumab will be used in a placebo controlled randomized study to treat severe chronic rhinosinusitis with nasal polyps

Detailed description: Chronic rhinosinusitis (CRS) has a prevalence of more than 10% in the United States and Europe and is associated with several co-morbidities including asthma, acute infection, and obstructive sleep apnea. There are principally two forms of CRS namely with and without nasal polyps. CRS with nasal polyps (CRSwNP) in particular can be a severe and debilitating disease resulting in significant morbidity, complete anosmia, headaches, missed work, and hospitalizations. Not uncommonly, patients require chronic oral corticosteroids, multiple courses of antibiotics, and repeated surgical polypectomies to control participants' disease. Total health care expenditure for CRS (which includes both with and without polyps) is more than $60 billion annually in the United States accounting for as much as 5% of the total US health care budget. Annual direct and indirect costs to treat CRS in Europe is estimated to be similar to this amount but data is limited.

For CRSwNP patients suffering with severe and recurrent nasal polyps there are few treatment options. High dose topical nasal steroids and repeated surgical procedures do not halt progression in many patients. Allergen immunotherapy is often non-curative in this population. Similarly, due to the fact that CRSwNP is not exclusively an Immunoglobulin E (IgE) driven process, omalizumab was shown to have mixed benefit in this population. Likewise, omalizumab resulted in no reduction in polyp size among patients with Aspirin Exacerbated Respiratory Disease (AERD).

More typically chronic nasal polyp disease is an eosinophil mediated process. Patients with demonstrated elevations in serum and mucosal eosinophils tend to have more severe disease and higher nasal polyp recurrence rates. Clinical researchers have begun to recognize this connection. A recent Phase II study in Europe showed a reduction in polyp burden using mepolizumab anti-Interleukin (IL) 5 monoclonal antibody. Benralizumab which targets IL-5 receptor signaling has been shown to have powerful apoptotic effects on eosinophils and may likely prove to be even more efficacious. Because of its unique mechanism of action, benralizumab may have a profound impact on reducing mucosal eosinophils resulting in great benefit to patients suffering with severe nasal polyps refractory to standard treatment.

Benralizumab has been shown to be efficacious treating severe asthmatics with eosinophilia. The unique mechanism of action of benralizumab targets the IL-5 receptor leading to degradation of signaling and apoptosis. This direct effect on eosinophils leads to reduction of proinflammatory processes in the asthmatic airways among those with elevated eosinophil counts. While many subjects with allergic asthma do indeed have concomitant local and systemic elevations in eosinophils, the primary driver of inflammation in allergic asthmatics is IgE and IL-4. Allergen immunotherapy and anti-IgE therapy (omalizumab) has long been known to be effective in these atopic individuals. However, a significant portion of non-asthmatics respond poorly to these IgE targeted therapies.

In a similar manner, chronic rhinosinusitis with nasal polyps (CRSwNP) is a disease often associated with atopy and propagated by IgE/IL-4 mediated inflammation. However, more than 50% of patients with CRSwNP have no evidence of allergen sensitivity. Nasal and sinus inflammation in these non-atopic individuals is often characterized by IL-5 upregulation, eosinophilia, leukotrienes, and more severe polyps. These individuals tend to have more aggressive disease requiring frequent surgeries, high dose intranasal budesonide irrigation, and oral steroids yet the polyps more often than not are persistent and may return post surgery. In a subset of patients, concomitant aspirin sensitivity can be managed with aspirin desensitization, however this approach is not always effective and can also be cumbersome. A more universal and potentially more efficient approach to treating severe polyps is to target eosinophils directly using a monoclonal antibody. Previous reports have shown some benefit targeting IL-5 ligand itself with mepolizumab but the potential benefit of directly eliminating eosinophils by shutting down cellular signaling with benralizumab would be expected to have a more dramatic effect and needs to be investigated.

Eligibility criteria: Inclusion Criteria:

* Adults aged 18-75
* Severe bilateral nasal polyps with average endoscopic score of at least 5
* Blood eosinophil count of at least 300/ul at screening
* At least 1000mg prednisone (or equivalent) over the previous 12 months to control symptoms
* At least one prior nasal surgical polypectomy
* Informed Consent: Able to give written informed consent prior to participation in the study, which will include the ability to comply with the requirements and restrictions listed in the consent form. Subjects must be able to read, comprehend, and write at a level sufficient to complete study related materials.
* Female subjects: Women of childbearing potential (WOCBP) must use an effective form of birth control (confirmed by the Investigator). Effective forms of birth control include: true sexual abstinence, a vasectomized sexual partner, Implanon, female sterilization by tubal occlusion, any effective Intra-uterine device (IUD) intrauterine device/ levonogestrel Intrauterine system (IUS), Depo-Provera(tm) injections, oral contraceptive, and Evra Patch(tm) or Nuvaring(tm). WOCBP must agree to use effective method of birth control, as defined above, from enrolment, throughout the study duration and within 16 weeks after last dose of IP, and have negative serum pregnancy test result on Visit 0.
* Women not of childbearing potential are defined as women who are either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrheic for 12 months prior to the planned date of visit -1 without an alternative medical cause. The following age-specific requirements apply:
* Women \<50 years old would be considered postmenopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatment and follicle stimulating hormone (FSH) levels in the postmenopausal range.
* 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 with or without spermicide, vasectomy) from Visit 0 until 16 weeks after their last dose.

Exclusion Criteria:

* Immunosuppression other than oral steroids in the past 3 months
* Allergen immunotherapy build up phase in the past 3 months
* Symptomatic or untreated life threatening cardiopulmonary disorders
* Subjects who are febrile (≥38°C; ≥100.4°F);
* History of cancer: Subjects who have had basal cell carcinoma, localized squamous cell carcinoma of the skin, or in situ carcinoma of the cervix are eligible provided that the subject is in remission and curative therapy was completed at least 12 months prior to the date informed consent, and assent when applicable was obtained. Subjects who have had other malignancies are eligible provided that the subject is in remission and curative therapy was completed at least 5 years prior to the date informed consent, and assent when applicable, was obtained.
* A helminth parasitic infection diagnosed within 24 weeks prior to the date informed consent is obtained that has not been treated with, or has failed to respond to standard of care therapy.
* Pregnant or nursing
* If female and of child-bearing potential, positive pregnancy test or failure to adhere to acceptable method of contraception (with \<1% failure rate) during the study and for four months after the study.
* Receipt of any investigational non biologic within 30 days or 5 half-lives prior to visit 0, whichever is longer.
* A history of known immunodeficiency disorder including a positive human immunodeficiency virus (HIV) test.
* Any other medical illness that precludes study involvement
* Positive hepatitis B surface antigen, or hepatitis C virus antibody serology, or a positive medical history for hepatitis B or C. Subjects with a history of hepatitis B vaccination without history of hepatitis B are allowed to be enrolled.
* Patients who are currently receiving or have previously received benralizumab or any other type of anti-interleukin therapy (i.e. mepolizumab, reslizumab, lebrikizumab etc.) within the last 4 months or 5 half-lives whichever is longer.
* History of anaphylaxis to any biologic therapy or vaccine.
* Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent is obtained.
* Receipt of live attenuated vaccines within 30 days of starting the study drug.

Primary outcomes:
measure: Change in Nasal Polyp Score
timeFrame: Week 5 and Week 25
Secondary outcomes:
measure: Change in Nasal Polyp Size as Assessed by the Lund Mackay Score
timeFrame: Week 5 and Week 25
measure: Change in Symptom Severity Score as Assessed by the Sino-nasal Outcome Test
timeFrame: Treatment Week 0 and Week 20
measure: Change in The University of Pennsylvania Smell Identification Test Score
timeFrame: Week 5 and Week 25
measure: Change in Absolute Eosinophil Count
timeFrame: Assessed at Treatment Week 0 and Week 20
measure: Utilization of Prednisone as a Rescue Medication
timeFrame: 20 weeks
measure: Time to Surgery
timeFrame: 24 weeks
measure: Number of Participants Who Dropped Out
timeFrame: Up to 29 weeks
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Johns Hopkins University School of Medicine
state: Maryland
Study officials:
affiliation: Johns Hopkins University
name: Jody Tversky, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Geng B, Dilley M, Anterasian C. Biologic Therapies for Allergic Rhinitis and Nasal Polyposis. Curr Allergy Asthma Rep. 2021 Jun 10;21(6):36. doi: 10.1007/s11882-021-01013-y.
citation: Tversky J, Lane AP, Azar A. Benralizumab effect on severe chronic rhinosinusitis with nasal polyps (CRSwNP): A randomized double-blind placebo-controlled trial. Clin Exp Allergy. 2021 Jun;51(6):836-844. doi: 10.1111/cea.13852. Epub 2021 Feb 27.