Trial of Verapamil in Chronic Rhinosinusitis
Açar sözlər
Mücərrəd
Təsvir
Chronic rhinosinusitis (CRS) impacts more than 30 million Americans resulting in $6.9 to $9.9 billion in annual healthcare expenditures and $12.8 billion in productivity costs. The prevalence of Chronic Rhinosinusitis with Nasal Polyps(CRSwNP) in Europe has been estimated to be 2-4.3% and is thought to be similar in the United States. Corticosteroids remain the mainstay of treatment although novel therapies are being developed based on an evolving understanding of the inflammatory pathways involved in disease pathogenesis. CRSwNP is characterized by the presence of edematous polypoid mucosa and predominantly eosinophilic inflammation. Recent evidence has focused on the sinonasal epithelial cell as a primary driver of the local dysregulated immune response through secretion of type 2 helper T-cell(Th2) promoting cytokines. While these studies suggest that epithelial cells are capable of orchestrating a local immune response, the mechanisms responsible for regulating cytokine secretion are poorly understood and may be influenced by the efflux function of epithelial P-glycoprotein(P-gp).
P-gp is a 170 kiloDalton membrane protein which belongs to sub-family B of the adenosine triphosphate(ATP)-binding cassette(ABC) transporter superfamily. P-gp utilizes ATP hydrolysis to transport a wide range of substrates across the plasma membrane. P-gp mediated transport has been observed in the regulation of cytokine secretion in both human T-cells as well as sinonasal epithelial cells implicating a potential immunomodulatory role. Studies by our group have demonstrated that P-gp is overexpressed in the mucosa of patients with Th2 skewed CRS endotypes including CRSwNP and is capable of regulating the secretion of Th2 polarizing cytokines. Together, these findings suggest that P-gp participates in the non-canonical regulation of cytokine secretion within CRSwNP and may thereby represent a druggable target.
Verapamil Hydrochloride(HCl) was one of the first inhibitors of P-gp to be identified in 1982 and also functions as a calcium channel blocker(CCB). Verapamil has since been categorized as a first generation P-gp inhibitor as more potent and selective 2nd and 3rd generation molecules were subsequently developed for use as chemotherapy sensitizers. Several studies, including those by our group, have reported that Verapamil is capable of modulating inflammatory responses in human T-cells, animal models of asthma, and nasal polyps. Using an organotypic explant model, we have previously shown that Verapamil has similar effects to dexamethasone in its ability to abrogate Interleukin(IL)-5, IL-6, and Thymic Stromal Lymphopoietin secretion. While Verapamil is cardioactive, it is considered the first-line prophylactic drug for cluster headache and is usually well tolerated by otherwise healthy patients.
In light of our prior studies demonstrating the immunomodulatory role of P-gp in promoting Th2 skewing cytokine secretion in CRSwNP, we hypothesized that low dose Verapamil HCl monotherapy would be safe and effective in the treatment of CRSwNP.
Tarixlər
Son Doğrulandı: | 04/30/2018 |
İlk təqdim: | 05/10/2015 |
Təxmini qeydiyyat təqdim edildi: | 05/21/2015 |
İlk Göndərmə: | 05/26/2015 |
Son Yeniləmə Göndərildi: | 05/15/2018 |
Son Yeniləmə Göndərildi: | 06/13/2018 |
İlk təqdim edilmiş nəticələrin tarixi: | 08/28/2016 |
İlk təqdim edilmiş QC nəticələrinin tarixi: | 10/26/2016 |
İlk göndərilən nəticələrin tarixi: | 12/27/2016 |
Həqiqi Təhsilin Başlama Tarixi: | 04/30/2015 |
Təxmini İlkin Tamamlanma Tarixi: | 02/29/2016 |
Təxmini İşin Tamamlanma Tarixi: | 04/30/2017 |
Vəziyyət və ya xəstəlik
Müdaxilə / müalicə
Drug: Verapamil HCl
Other: Control
Faza
Qol Qrupları
Qol | Müdaxilə / müalicə |
---|---|
Experimental: Treatment Verapamil HCl, capsules for oral administration, 80mg, TID, for 8 weeks | |
Placebo Comparator: Control Placebo, capsules for oral administration, TID, for 8 weeks | Other: Control Capsule with the same characteristics (size, color, smell) as Verapamil HCl. |
Experimental: Open Label Verapamil HCl, capsules for oral administration, 80mg, TID, for 1 year |
Uyğunluq Kriteriyaları
Təhsil üçün uyğun yaşlar | 18 Years Üçün 18 Years |
Təhsilə Uyğun Cinslər | All |
Sağlam Könüllüləri qəbul edir | Bəli |
Kriteriyalar | Inclusion Criteria: 1. Patients presenting to the Massachusetts Eye and Ear Sinus Center 2. Age 18-80 yrs old 3. Diagnosed with Chronic Rhinosinusitis with Nasal Polyps according to the EPOS 2012 consensus criteria Exclusion Criteria: 1. Patients with the following comorbidities: - GI Hypomotility - Heart Failure - Liver Failure - Kidney Disease - Muscular Dystrophy - Pregnant or Nursing Females - Steroid Dependency 2. Patients taking the following medications: - Aspirin - Beta-blockers - Cimetidine(Tagamet) - Clarithromycin(Biaxin) - Cyclosporin - Digoxin - Disopyramide(Norpace) - Diuretics - Erythromycin - Flecainide - HIV Protease Inhibitors(Indinavir, Nelfinavir, Ritonavir) - Quinidine - Lithium - Pioglitazone - Rifampin - St Johns Wort 3. Patients with cardiac or conduction abnormality picked up by screening EKG |
Nəticə
İlkin nəticə tədbirləri
1. Subjective Sinonasal Symptoms on Sinonasal Outcomes Test-22(SNOT-22) [baseline to week 8]
2. Subjective Sinonasal Symptoms on 10cm Visual Analogue Scale(VAS) [baseline to week 8]
3. Subjective Sinonasal Symptoms on Sinonasal Outcomes Test-22(SNOT-22) [baseline to week 56]
4. Subjective Sinonasal Symptoms on 10cm Visual Analogue Scale(VAS) [baseline to week 56]
İkincili Nəticə Tədbirləri
1. Objective Sinonasal Symptoms on Lund-Kennedy Score(LKS) [baseline to week 8]
2. Objective Sinonasal Symptoms on Lund-McKay Score(LMS) [Week 8]
Digər nəticə tədbirləri
1. Heart Rate [Mean change between baseline and week 8 measurements.]
2. Systolic Blood Pressure [Mean change between baseline and week 8 measurements]
3. Diastolic Blood Pressure [Mean change between baseline and week 8 measurements]