Trial of Verapamil in Chronic Rhinosinusitis

May 16, 2018 updated by: Benjamin Bleier

Randomized Double Blind Placebo Controlled Trial of Verapamil in Chronic Rhinosinusitis

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

29

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Massachusetts Eye and Ear Infirmary

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment
Verapamil HCl, capsules for oral administration, 80mg, TID, for 8 weeks
Drug: Verapamil HCl
Verapamil represents a calcium channel blocker which binds to the alpha subunit of L-type voltage dependent calcium (Cav1) channels thereby blocking the influx of calcium ions into the host cell. While Verapamil is classically used to promote the relaxation of cardiac and smooth muscle cells, recent evidence has suggested that it may also function as an immunomodulator in astrocytes, hepatocytes, and T-cells. Further research has demonstrated that Verapamil is capable of specifically reducing Th2 associated inflammation in asthma. These findings raise the provocative question as to whether Verapamil could also be effective in reducing inflammation in chronic rhinosinusitis with nasal polyps.
Other Names:
  • Verapamil
Placebo Comparator: Control
Placebo, capsules for oral administration, TID, for 8 weeks
Other: Placebo
Capsule with the same characteristics (size, color, smell) as Verapamil HCl.
Experimental: Open Label
Verapamil HCl, capsules for oral administration, 80mg, TID, for 1 year
Drug: Verapamil HCl
Verapamil represents a calcium channel blocker which binds to the alpha subunit of L-type voltage dependent calcium (Cav1) channels thereby blocking the influx of calcium ions into the host cell. While Verapamil is classically used to promote the relaxation of cardiac and smooth muscle cells, recent evidence has suggested that it may also function as an immunomodulator in astrocytes, hepatocytes, and T-cells. Further research has demonstrated that Verapamil is capable of specifically reducing Th2 associated inflammation in asthma. These findings raise the provocative question as to whether Verapamil could also be effective in reducing inflammation in chronic rhinosinusitis with nasal polyps.
Other Names:
  • Verapamil

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Subjective Sinonasal Symptoms on Sinonasal Outcomes Test-22(SNOT-22)
Time Frame: baseline to week 8
Minimum Score: 0 Maximum Score: 110 A higher score indicates a worse outcome
baseline to week 8
Subjective Sinonasal Symptoms on 10cm Visual Analogue Scale(VAS)
Time Frame: baseline to week 8
Minimum Score: 0 Maximum Score: 100 A higher score indicates a worse outcome.
baseline to week 8
Subjective Sinonasal Symptoms on Sinonasal Outcomes Test-22(SNOT-22)
Time Frame: baseline to week 56
Minimum Score: 0 Maximum Score: 110 A higher score indicates a worse outcome
baseline to week 56
Subjective Sinonasal Symptoms on 10cm Visual Analogue Scale(VAS)
Time Frame: baseline to week 56
Minimum Score: 0 Maximum Score: 100 A higher score indicates a worse outcome.
baseline to week 56

Secondary Outcome Measures

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

Other Outcome Measures

Outcome Measure
Time Frame
Heart Rate
Time Frame: Mean change between baseline and week 8 measurements.
Mean change between baseline and week 8 measurements.
Systolic Blood Pressure
Time Frame: Mean change between baseline and week 8 measurements
Mean change between baseline and week 8 measurements
Diastolic Blood Pressure
Time Frame: Mean change between baseline and week 8 measurements
Mean change between baseline and week 8 measurements

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Benjamin Bleier

Investigators

  • Principal Investigator: Benjamin S Bleier, MD, Massachusetts Eye and Ear Infirmary

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2015

Primary Completion (Actual)

March 1, 2016

Study Completion (Actual)

May 1, 2017

Study Registration Dates

First Submitted

May 11, 2015

First Submitted That Met QC Criteria

May 22, 2015

First Posted (Estimate)

May 27, 2015

Study Record Updates

Last Update Posted (Actual)

June 14, 2018

Last Update Submitted That Met QC Criteria

May 16, 2018

Last Verified

May 1, 2018

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 15-009H

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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