Trial of Verapamil in Chronic Rhinosinusitis

Not Applicable

Terminated

Conditions: Nasal Polyps
Sinusitis

Interventions: Drug: Verapamil HCl
Other: Placebo

Registration Number: NCT02454608

Lead Sponsor: Benjamin Bleier

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 29

Inclusion Criteria

Patients presenting to the Massachusetts Eye and Ear Sinus Center
Age 18-80 yrs old
Diagnosed with Chronic Rhinosinusitis with Nasal Polyps according to the EPOS 2012 consensus criteria

Exclusion Criteria

Patients with the following comorbidities:
- GI Hypomotility
- Heart Failure
- Liver Failure
- Kidney Disease
- Muscular Dystrophy
- Pregnant or Nursing Females
- Steroid Dependency
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
Patients with cardiac or conduction abnormality picked up by screening EKG

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment	Verapamil HCl	Verapamil HCl, capsules for oral administration, 80mg, TID, for 8 weeks
Control	Placebo	Placebo, capsules for oral administration, TID, for 8 weeks
Open Label	Verapamil HCl	Verapamil HCl, capsules for oral administration, 80mg, TID, for 1 year

Primary Outcome Measures

Name	Time	Method
Subjective Sinonasal Symptoms on Sinonasal Outcomes Test-22(SNOT-22)	baseline to week 56	Minimum Score: 0 Maximum Score: 110 A higher score indicates a worse outcome
Subjective Sinonasal Symptoms on 10cm Visual Analogue Scale(VAS)	baseline to week 56	Minimum Score: 0 Maximum Score: 100 A higher score indicates a worse outcome.

Secondary Outcome Measures

Name	Time	Method
Objective Sinonasal Symptoms on Lund-Kennedy Score(LKS)	baseline to week 8	Minimum Score: 0 Maximum Score: 12 Higher value represents worse outcome.
Objective Sinonasal Symptoms on Lund-McKay Score(LMS)	Week 8	Minimum Score: 0 Maximum Score: 24 Higher value represents worse outcome.