Trial of Topical Verapamil in Chronic Rhinosinusitis With Nasal Polyps

Phase Ib/II Clinical Trial of Topical Verapamil Hydrochloride for Chronic Rhinosinusitis With Nasal Polyps

Verapamil is an L-type calcium channel blocker(CCB) which has been shown to reduce inflammation in a variety of tissues. Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by eosinophilic inflammation as well as P-gp overexpression. A previous trial of oral Verapamil showed preliminary efficacy for the treatment of CRSwNP. The goal of this study is to evaluate the safety and efficacy of intranasal Verapamil in CRSwNP. The study was initially approved as a Phase Ib/II, but only the Phase Ib portion was completed as part of this protocol.

CRSwNP is a prevalent disease associated with major direct and indirect costs. Acute and Chronic Rhinosinusitis are estimated to affect up to 16% of the US population. They account for approximately 11 million or 1% of all office visits per year in the US and are the most common cause for antibiotic prescriptions in the community. CRS alone 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 subset of patients in Europe with CRSwNP has been estimated to be between 2 and 4.3% and is thought to be similar in the US. This population remains one of the most challenging subgroups of CRS to manage effectively. 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). Studies by the investigator's 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. The investigator's group therefore undertook a randomized, double-blind, placebo-controlled trial to test the efficacy of low dose oral Verapamil HCl, a known first generation P-gp inhibitor, for the treatment of CRSwNP. Our findings demonstrated significant efficacy in both of the primary and secondary endpoints with no significant side effects. However, a logistic regression analysis revealed two important relationships between baseline characteristics and efficacy. First, patients with elevated BMI had significantly lower improvements in the Sinonasal Outcome Test (SNOT-22) (p=0.01). The second is that patients with the highest total mucus P-gp levels experienced less benefit(p=0.01). While Verapamil HCl has significant potential for the treatment of CRSwNP through P-gp inhibition, higher doses must be achieved to extend the effect to patients with elevated BMIs and the highest levels of P-gp expression. As increasing oral dosing could result in cardiac side effects, topical delivery represents a promising alternative. As exosome bound P-gp may be more stable and representative of disease state than total mucus P-gp concentration, exosomal P-gp demands further exploration as a novel biomarker of disease severity and drug response.

The phase Ib study will consist of an accelerated titration, intrapatient dose escalation cohort, with double-dose step design of Verapamil Hydrochloride. Intranasal BID for 1 week. Dose escalation will occur weekly as a doubling of the dose from 10-120mg Verapamil delivered in 240mL buffered normal saline. If a single, any course, dose-limiting toxicity (DLT) or second, any course, IT occurs, two additional patients will be recruited at that identified dose and Phase Ib will revert to a standard 3+3 design. If any patient un-enrolls while the dose escalation is still occurring, they will be replaced to maintain 3 patient cohorts. The maximal administered dose (MAD) will be considered that at which at least 2 DLTs or 4 ITs occur and the MTD will then be assigned to the immediate preceding dose.

Verapamil solution for injection, supplied in vials, will be utilized in a Neil Med Sinus Rinse of 240mL buffered normal saline.

Dose Limiting Toxicity will be defined as a development of 2nd or 3rd degree heart block as measured by an EKG. (Phase Ib primary outcome)

Inclusion Criteria: Patients presenting to the Mass Eye and Ear Sinus Center Age 18-80 yrs old Diagnosed with Chronic Rhinosinusitis with Nasal Polyps according to the EPOS 2012 consensus criteria Post-operative with a Lund-Kennedy Poly score of <4 Baseline SNOT-22 Score ≥ 30 Exclusion Criteria: Patients with the following comorbidities: GI Hypomotility Heart Failure Liver Failure Kidney Disease Muscular Dystrophy Pregnant or Nursing Females Steroid Dependency Hypertrophic Cardiomyopathy Any Atrial or Ventricular arrhythmia (ie. Atrial fibrillation, atrial flutter, etc..) Resting Heart Rate less than 60 beats per minute Baseline Systolic Blood Pressure less than 110 mmHg Baseline Diastolic Blood Pressure less than 70 mmHg Baseline Mean Arterial Pressure Less than 60 mmHg PR interval less than 0.12 seconds 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 Post-op patients with surgery within 3 months prior to enrollment.

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