Clinical trial NCT02454608: Trial of Verapamil in Chronic Rhinosinusitis
Official title: Randomized Double Blind Placebo Controlled Trial of Verapamil in Chronic Rhinosinusitis
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Sinusitis
Nasal Polyps
Lead sponsor: Massachusetts Eye and Ear Infirmary
Sponsor class: OTHER
First posted: 2015-05-27
Enrollment: 29
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Verapamil is an L-type calcium channel blocker(CCB) which has been shown to reduce inflammation in a variety of tissues. Verapamil has also been shown to improve eosinophilic inflammation in an animal model of asthma and also functions as a P-glycoprotein(P-gp) inhibitor. A major subtype of chronic rhinosinusitis(CRS) is characterized by eosinophilic inflammation as well as P-gp overexpression. The goal of this study is to therefore see whether Verapamil may be used to treat CRS.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Subjective Sinonasal Symptoms on Sinonasal Outcomes Test-22(SNOT-22)
timeFrame: baseline to week 8
measure: Subjective Sinonasal Symptoms on 10cm Visual Analogue Scale(VAS)
timeFrame: baseline to week 8
measure: Subjective Sinonasal Symptoms on Sinonasal Outcomes Test-22(SNOT-22)
timeFrame: baseline to week 56
measure: Subjective Sinonasal Symptoms on 10cm Visual Analogue Scale(VAS)
timeFrame: baseline to week 56
Secondary outcomes:
measure: Objective Sinonasal Symptoms on Lund-Kennedy Score(LKS)
timeFrame: baseline to week 8
measure: Objective Sinonasal Symptoms on Lund-McKay Score(LMS)
timeFrame: Week 8
Other outcomes:
measure: Heart Rate
timeFrame: Mean change between baseline and week 8 measurements.
measure: Systolic Blood Pressure
timeFrame: Mean change between baseline and week 8 measurements
measure: Diastolic Blood Pressure
timeFrame: Mean change between baseline and week 8 measurements
Locations:
city: Boston
country: United States
facility: Massachusetts Eye and Ear Infirmary
state: Massachusetts
Study officials:
affiliation: Massachusetts Eye and Ear Infirmary
name: Benjamin S Bleier, MD
role: PRINCIPAL_INVESTIGATOR
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