Trial of Verapamil in Chronic Rhinosinusitis
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|ClinicalTrials.gov Identifier: NCT02454608|
Recruitment Status : Terminated (Evidence that the dose is insufficient.)
First Posted : May 27, 2015
Results First Posted : December 28, 2016
Last Update Posted : October 24, 2017
|Condition or disease||Intervention/treatment|
|Sinusitis Nasal Polyps||Drug: Verapamil HCl Other: Placebo|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||20 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Triple (Participant, Investigator, Outcomes Assessor)|
|Official Title:||Randomized Double Blind Placebo Controlled Trial of Verapamil in Chronic Rhinosinusitis|
|Study Start Date :||May 2015|
|Primary Completion Date :||March 2016|
|Study Completion Date :||March 2016|
Verapamil HCl, capsules for oral administration, 80mg, TID, for 8 weeks
Drug: Verapamil HCl
Verapamil represents a calcium channel blocker which binds to the alpha subunit of L-type voltage dependent calcium (Cav1) channels thereby blocking the influx of calcium ions into the host cell. While Verapamil is classically used to promote the relaxation of cardiac and smooth muscle cells, recent evidence has suggested that it may also function as an immunomodulator in astrocytes, hepatocytes, and T-cells. Further research has demonstrated that Verapamil is capable of specifically reducing Th2 associated inflammation in asthma. These findings raise the provocative question as to whether Verapamil could also be effective in reducing inflammation in chronic rhinosinusitis with nasal polyps.
Other Name: Verapamil
Placebo Comparator: Control
Placebo, capsules for oral administration, TID, for 8 weeks
Capsule with the same characteristics (size, color, smell) as Verapamil HCl.
- Subjective Sinonasal Symptoms on Sinonasal Outcomes Test-22(SNOT-22) [ Time Frame: baseline to week 8 ]Minimun Score: 0 Maximum Score: 110 A higher score indicates a worse outcome
- Subjective Sinonasal Symptoms on 10cm Visual Analogue Scale(VAS) [ Time Frame: baseline to week 8 ]Minimum Score: 0 Maximum Score: 100 A higher score indicates a worse outcome.
- Objective Sinonasal Symptoms on Lund-Kennedy Score(LKS) [ Time Frame: baseline to week 8 ]Minimum Score: 0 Maximum Score: 12 Higher value represents worse outcome.
- Objective Sinonasal Symptoms on Lund-McKay Score(LMS) [ Time Frame: Week 8 ]Minimum Score: 0 Maximum Score: 24 Higher value represents worse outcome.
- Heart Rate [ Time Frame: Mean change between baseline and week 8 measurements. ]
- Systolic Blood Pressure [ Time Frame: Mean change between baseline and week 8 measurements ]
- Diastolic Blood Pressure [ Time Frame: Mean change between baseline and week 8 measurements ]
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02454608
|United States, Massachusetts|
|Massachusetts Eye and Ear Infirmary|
|Boston, Massachusetts, United States, 02114|
|Principal Investigator:||Benjamin S Bleier, MD||Massachusetts Eye and Ear Infirmary|