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Trial of Topical Verapamil in Chronic Rhinosinusitis With Nasal Polyps

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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
Sponsor:
Information provided by (Responsible Party):
Benjamin Bleier, Massachusetts Eye and Ear Infirmary

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Sinusitis Nasal Polyps Drug: Verapamil Hydrochloride Intranasal Phase 1

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 6 participants
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.




Primary Outcome Measures :
  1. 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)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

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


Locations
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United States, Massachusetts
Massachusetts Eye and Ear
Boston, Massachusetts, United States, 02114
Sponsors and Collaborators
Benjamin Bleier
Investigators
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Principal Investigator: Benjamin S Bleier, MD Massachusetts Eye and Ear
  Study Documents (Full-Text)

Documents provided by Benjamin Bleier, Massachusetts Eye and Ear Infirmary:

Publications:

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Responsible Party: Benjamin Bleier, Principal Investigator, Massachusetts Eye and Ear Infirmary
ClinicalTrials.gov Identifier: NCT03102190    
Other Study ID Numbers: 17-002H
First Posted: April 5, 2017    Key Record Dates
Results First Posted: June 21, 2019
Last Update Posted: July 23, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Sinusitis
Nasal Polyps
Polyps
Pathological Conditions, Anatomical
Paranasal Sinus Diseases
Nose Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Otorhinolaryngologic Diseases
Verapamil
Anti-Arrhythmia Agents
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Calcium-Regulating Hormones and Agents
Physiological Effects of Drugs
Vasodilator Agents