Clinical trial NCT04430179: Dupilumab Severe Eosinophilic Chronic Sinusitis Without Nasal Polyposis
Official title: An Evaluation of Dupilumab in Patients With Severe Eosinophilic Chronic Sinusitis Without Nasal Polyposis
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Severe Eosinophilic Chronic Sinusitis Without Nasal Polyposis
Lead sponsor: University of South Florida
Sponsor class: OTHER
First posted: 2020-06-12
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Active drug vs placebo
Primary purpose: TREATMENT

Brief summary: The investigators will investigate the efficacy of dupilumab in patients with severe eosinophilic CRSsNP who are resistant to the conventional treatment with intranasal corticosteroids and have significantly extensive disease involving more than 2 sinuses bilaterally in sinus CT scan and Lund-Mackay sinus (LMK) CT score \>=10 at baseline.

Detailed description: The investigators will use high blood eosinophils (\>=200) as a biomarker for eosinophilic CRSsNP and investigate the efficacy of dupilumab in patients with severe eosinophilic CRSsNP who are resistant to the conventional treatment with intranasal corticosteroids and have significantly extensive disease involving more than 2 sinuses bilaterally in sinus CT scan and Lund-Mackay sinus (LMK) CT score \>=10 at baseline. In addition, the investigators will have a prespecified enrollment goal of at least 50% of patients with type 2 inflammatory diseases such as asthma, allergic rhinitis, and/or atopic dermatitis on the basis of patient-reported history and will stratify subject numbers between dupilumab treatment and placebo group.

Eligibility criteria: Inclusion Criteria:

* Age 18 or older
* LMK-CT score ≥ 10 (out of maximum of 24) at screening.
* Bilateral sinusitis with at least more than 2 sinus involvement despite completion of a prior intranasal corticosteroid (INCS) treatment for at least 8 weeks prior to screening
* Presence of at least two of the following symptoms prior to screening:
* Nasal blockage/obstruction/congestion
* Nasal discharge (anterior/posterior nasal drip)
* Facial pain/pressure
* Reduction or loss of smell
* Must have Eosinophilic CRSsNP (blood eos ≥ 200) within 6 months prior to screening
* Able and willing to undergo regular intervention as well as evaluation per study protocol
* Must agree not to participate in a clinical study involving another investigational drug or device throughout the duration of this study
* Must be competent to understand the information given in IRB approved ICF and must sign the form prior to the initiation of any study procedure

Exclusion Criteria:

* Age \< 18
* With CRS with nasal polyps
* Treated in any clinical trial of dupilumab
* Has taken:

  1. Biologic therapy/systemic immunosuppressant to treat inflammatory disease or autoimmune disease (eg, rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, etc) within 2 months before screening or 5 half-lives, whichever is longer
  2. An experimental monoclonal antibody within five half-lives or within 6 months before screening if the half-life is unknown
  3. Anti-immunoglobulin E (IgE) therapy (omalizumab) within 130 days prior to screening
  4. Leukotriene antagonists/modifiers unless patient is on a continuous treatment for at least 30 days prior to screening
  5. Initiation of allergen immunotherapy within 3 months prior to screening or a plan to begin therapy or change its dose during the run-in period or the randomized treatment period
* Have had a sino-nasal surgery changing the lateral wall structure of the nose making impossible the evaluation of NPS
* Patients with conditions/concomitant diseases making them non-evaluable at screening or for the primary efficacy endpoint such as:

  1. Antrochoanal polyps
  2. Nasal septal deviation that would occlude at least one nostril
  3. Acute sinusitis, nasal infection or upper respiratory infection at screening
  4. Ongoing rhinitis medicamentosa
  5. Allergic granulomatous angiitis (Churg-Strauss syndrome), granulomatosis with polyangiitis (Wegener's granulomatosis), Young's syndrome, Kartagener's syndrome or other dyskinetic ciliary syndromes, concomitant cystic fibrosis
  6. Radiologic suspicion, or confirmed invasive or expansive fungal rhinosinusitis
* With co-morbid asthma are excluded if forced expiratory volume (FEV1) is 50% (of predicted normal) or less
* With known active bacterial, viral, fungal, mycobacterial infection, or other infection or any major episode of infection that required hospitalization or treatment with IV antibiotics within 30 days of screening or during screening or oral antibiotics within 14 days prior to screening. Fungal infection of nail beds is allowed
* Have human immunodeficiency virus/acquired immune deficiency syndrome
* Have acute or chronic hepatitis B/hepatitis C infection
* History of an opportunistic infection (eg, pneumocystis carinii, cryptococcal meningitis, progressive multifocal leukoencephalopathy) or serious bacterial, viral, or fungal infections (eg, disseminated herpes simplex, disseminated herpes zoster) and requiring IV medication(s) ≤ 3 weeks prior to randomization
* History of or currently active primary or secondary immunodeficiency
* History of cancer within the last 5 years, including solid tumors and hematological malignancies (except basal cell and in situ squamous cell carcinomas of the skin that have been excised and resolved) or colonic mucosal dysplasia
* History of lymphoproliferative disorder, lymphoma, leukemia, myeloproliferative disorder, or multiple myeloma
* History of alcohol or drug abuse within 1 year prior to randomization
* Receipt of live vaccine within 4 weeks prior to randomization
* Pregnant or breastfeeding
* Participation in another clinical study or treatment with an investigational drug or device
* Serious or active medical or psychiatric condition which, in the opinion of the Investigator, may interfere with treatment, assessment, or compliance with the protocol

Primary outcomes:
measure: Change in Lund-Mackay sinus computed tomography (LMK-CT) score
timeFrame: 24 weeks
Secondary outcomes:
measure: Change in participant-reported symptoms scores of sinusitis
timeFrame: 24 weeks
measure: Change in visual analogue scale score for sinusitis
timeFrame: 24 weeks
measure: Change in nasal peak inspiratory flow
timeFrame: 24 weeks
measure: Change in University of Pennsylvania smell identification test (UPSIT) scores
timeFrame: 24 weeks
measure: Time to first response in LMK-CT score
timeFrame: 24 weeks
measure: Change in sinonasal outcome test (SNOT-22) score
timeFrame: 24 weeks
measure: Change in biomarkers concentrations in nasal secretion measured by enzyme-linked immunosorbent assay (ELISA)
timeFrame: 24 weeks
Other outcomes:
Locations:
city: Tampa
country: United States
facility: University of South Florida Asthma, Allergy and Immunology
state: Florida
Study officials:
affiliation: University of South Florida
name: Seong Cho, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Kim DY, Lee SH, Carter RG, Kato A, Schleimer RP, Cho SH. A Recently Established Murine Model of Nasal Polyps Demonstrates Activation of B Cells, as Occurs in Human Nasal Polyps. Am J Respir Cell Mol Biol. 2016 Aug;55(2):170-5. doi: 10.1165/rcmb.2016-0002RC.
citation: Tokunaga T, Sakashita M, Haruna T, Asaka D, Takeno S, Ikeda H, Nakayama T, Seki N, Ito S, Murata J, Sakuma Y, Yoshida N, Terada T, Morikura I, Sakaida H, Kondo K, Teraguchi K, Okano M, Otori N, Yoshikawa M, Hirakawa K, Haruna S, Himi T, Ikeda K, Ishitoya J, Iino Y, Kawata R, Kawauchi H, Kobayashi M, Yamasoba T, Miwa T, Urashima M, Tamari M, Noguchi E, Ninomiya T, Imoto Y, Morikawa T, Tomita K, Takabayashi T, Fujieda S. Novel scoring system and algorithm for classifying chronic rhinosinusitis: the JESREC Study. Allergy. 2015 Aug;70(8):995-1003. doi: 10.1111/all.12644. Epub 2015 May 26.
citation: Hu Y, Cao PP, Liang GT, Cui YH, Liu Z. Diagnostic significance of blood eosinophil count in eosinophilic chronic rhinosinusitis with nasal polyps in Chinese adults. Laryngoscope. 2012 Mar;122(3):498-503. doi: 10.1002/lary.22507. Epub 2012 Jan 17.
citation: Ho J, Hamizan AW, Alvarado R, Rimmer J, Sewell WA, Harvey RJ. Systemic Predictors of Eosinophilic Chronic Rhinosinusitis. Am J Rhinol Allergy. 2018 Jul;32(4):252-257. doi: 10.1177/1945892418779451. Epub 2018 Jun 4.
citation: Thwaites RS, Gunawardana NC, Broich V, Mann EH, Ahnstrom J, Campbell GA, Lindsley S, Singh N, Tunstall T, Lane DA, Openshaw PJ, Hawrylowicz CM, Hansel TT. Biphasic activation of complement and fibrinolysis during the human nasal allergic response. J Allergy Clin Immunol. 2018 May;141(5):1892-1895.e6. doi: 10.1016/j.jaci.2018.01.022. Epub 2018 Feb 7. No abstract available.
citation: Hopkins C, Browne JP, Slack R, Lund VJ, Topham J, Reeves BC, Copley LP, Brown P, van der Meulen JH. Complications of surgery for nasal polyposis and chronic rhinosinusitis: the results of a national audit in England and Wales. Laryngoscope. 2006 Aug;116(8):1494-9. doi: 10.1097/01.mlg.0000230399.24306.50.
citation: Gevaert P, Lang-Loidolt D, Lackner A, Stammberger H, Staudinger H, Van Zele T, Holtappels G, Tavernier J, van Cauwenberge P, Bachert C. Nasal IL-5 levels determine the response to anti-IL-5 treatment in patients with nasal polyps. J Allergy Clin Immunol. 2006 Nov;118(5):1133-41. doi: 10.1016/j.jaci.2006.05.031. Epub 2006 Sep 26.
citation: Gevaert P, Calus L, Van Zele T, Blomme K, De Ruyck N, Bauters W, Hellings P, Brusselle G, De Bacquer D, van Cauwenberge P, Bachert C. Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma. J Allergy Clin Immunol. 2013 Jan;131(1):110-6.e1. doi: 10.1016/j.jaci.2012.07.047. Epub 2012 Sep 27.
citation: Gevaert P, Van Bruaene N, Cattaert T, Van Steen K, Van Zele T, Acke F, De Ruyck N, Blomme K, Sousa AR, Marshall RP, Bachert C. Mepolizumab, a humanized anti-IL-5 mAb, as a treatment option for severe nasal polyposis. J Allergy Clin Immunol. 2011 Nov;128(5):989-95.e1-8. doi: 10.1016/j.jaci.2011.07.056. Epub 2011 Sep 28.
citation: Benjamin MR, Stevens WW, Li N, Bose S, Grammer LC, Kern RC, Tan BK, Conley DB, Smith SS, Welch KC, Schleimer RP, Peters AT. Clinical Characteristics of Patients with Chronic Rhinosinusitis without Nasal Polyps in an Academic Setting. J Allergy Clin Immunol Pract. 2019 Mar;7(3):1010-1016. doi: 10.1016/j.jaip.2018.10.014. Epub 2018 Oct 25.
citation: Wang X, Zhang N, Bo M, Holtappels G, Zheng M, Lou H, Wang H, Zhang L, Bachert C. Diversity of TH cytokine profiles in patients with chronic rhinosinusitis: A multicenter study in Europe, Asia, and Oceania. J Allergy Clin Immunol. 2016 Nov;138(5):1344-1353. doi: 10.1016/j.jaci.2016.05.041. Epub 2016 Jul 15.
citation: Stevens WW, Peters AT, Tan BK, Klingler AI, Poposki JA, Hulse KE, Grammer LC, Welch KC, Smith SS, Conley DB, Kern RC, Schleimer RP, Kato A. Associations Between Inflammatory Endotypes and Clinical Presentations in Chronic Rhinosinusitis. J Allergy Clin Immunol Pract. 2019 Nov-Dec;7(8):2812-2820.e3. doi: 10.1016/j.jaip.2019.05.009. Epub 2019 May 22.
citation: Han DH, Kim SW, Cho SH, Kim DY, Lee CH, Kim SS, Rhee CS. Predictors of bronchial hyperresponsiveness in chronic rhinosinusitis with nasal polyp. Allergy. 2009 Jan;64(1):118-22. doi: 10.1111/j.1398-9995.2008.01841.x. Epub 2008 Dec 17.