Trial of Topical Verapamil in Chronic Rhinosinusitis With Nasal Polyps
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|ClinicalTrials.gov Identifier: NCT03102190|
Recruitment Status : Terminated (Phase II funding not available)
First Posted : April 5, 2017
Results First Posted : June 21, 2019
Last Update Posted : July 23, 2019
|Condition or disease||Intervention/treatment||Phase|
|Sinusitis Nasal Polyps||Drug: Verapamil Hydrochloride Intranasal||Phase 1|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||6 participants|
|Intervention Model:||Sequential Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase Ib/II Clinical Trial of Topical Verapamil Hydrochloride for Chronic Rhinosinusitis With Nasal Polyps|
|Actual Study Start Date :||June 5, 2017|
|Actual Primary Completion Date :||March 26, 2018|
|Actual Study Completion Date :||March 26, 2018|
Experimental: Phase Ib
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.
Drug: Verapamil Hydrochloride Intranasal
Verapamil solution for injection, supplied in vials, will be utilized in a Neil Med Sinus Rinse of 240mL buffered normal saline.
- Number of Participants With Dose Limiting Toxicity [ Time Frame: 1-8 weeks ]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)
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): NCT03102190
|United States, Massachusetts|
|Massachusetts Eye and Ear|
|Boston, Massachusetts, United States, 02114|
|Principal Investigator:||Benjamin S Bleier, MD||Massachusetts Eye and Ear|