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Benralizumab Effect on Severe Chronic Rhinosinusitis With Eosinophilic Polyposis

Yalnız qeydiyyatdan keçmiş istifadəçilər məqalələri tərcümə edə bilərlər
Giriş / Qeydiyyatdan keçin
Bağlantı panoya saxlanılır
StatusTamamlandı
Sponsorlar
Johns Hopkins University

Açar sözlər

Mücərrəd

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

Təsvir

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.

Tarixlər

Son Doğrulandı: 02/29/2020
İlk təqdim: 08/16/2017
Təxmini qeydiyyat təqdim edildi: 02/21/2018
İlk Göndərmə: 02/28/2018
Son Yeniləmə Göndərildi: 03/30/2020
Son Yeniləmə Göndərildi: 04/01/2020
Həqiqi Təhsilin Başlama Tarixi: 06/30/2017
Təxmini İlkin Tamamlanma Tarixi: 12/31/2019
Təxmini İşin Tamamlanma Tarixi: 01/31/2020

Vəziyyət və ya xəstəlik

Chronic Rhinosinusitis (Diagnosis)
Nasal Polyps
Eosinophilia

Müdaxilə / müalicə

Drug: Benralizumab treatment group

Drug: Placebo group

Faza

Faza 2

Qol Qrupları

QolMüdaxilə / müalicə
Active Comparator: Benralizumab treatment group
Benralizumab Active treatment group delivered subcutaneously
Drug: Benralizumab treatment group
30mg Benralizumab will be delivered subcutaneously
Placebo Comparator: Placebo group
Placebo treatment group delivered subcutaneously
Drug: Placebo group
Subcutaneous placebo injection

Uyğunluq Kriteriyaları

Təhsil üçün uyğun yaşlar 18 Years Üçün 18 Years
Təhsilə Uyğun CinslərAll
Sağlam Könüllüləri qəbul edirBəli
Kriteriyalar

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.

Nəticə

İlkin nəticə tədbirləri

1. Nasal Polyp Size [24 weeks]

Reduction in endoscopic nasal polyp score after 6 months of treatment

İkincili Nəticə Tədbirləri

1. Nasal polyp size by CT [24 weeks]

Lund-Mackay (LM) CT scan of sinus will be used to determine nasal polyp size. Each of four sinuses are graded 0-3 on each side (total range 0-24). 0 (no abnormality) (partial opacification) or (complete opacification)

2. Clinical Survey [24 weeks]

Sino-nasal Outcome Test (SNOT-22) nasal symptoms score. 22 questions each scored 0-5 (no problem - as bad as it can be) for a total range of 0-110.

3. Smell Test [24 weeks]

UPSIT smell test. 40 questions with four choices each. Number of correct answers range 0-40.

4. Blood Test [24 weeks]

Complete Blood Count (CBC) to determine absolute eosinophil count. Range 30-300/uL.

5. Rescue Medication Use [Up to 24 weeks]

Rescue Medication Score. Rescue medications include triamcinolone twice daily, and Prednisone 20mg for five days which will be given only as needed periodically. Score ranges from 0-20. (0=none, 5=triamcinolone nasal daily, 10=triamcinolone nasal BID, 20=prednisone 20mg for five days)

6. Time to Surgery [24 weeks]

Time to nasal polyp surgery. Measured in months starting after last injection.

7. Drop Out Rate [Up to 24 weeks]

Drop Out Rate. Calculated continuously throughout the study up to 24 weeks.

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