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Trial of Verapamil in Chronic Rhinosinusitis

This study has been terminated.
(Evidence that the dose is insufficient.)
Sponsor:
Information provided by (Responsible Party):
Benjamin Bleier, Massachusetts Eye and Ear Infirmary
ClinicalTrials.gov Identifier:
NCT02454608
First received: May 11, 2015
Last updated: March 24, 2017
Last verified: March 2017
  Purpose
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.

Condition Intervention
Sinusitis Nasal Polyps Drug: Verapamil HCl Other: Placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Randomized Double Blind Placebo Controlled Trial of Verapamil in Chronic Rhinosinusitis

Resource links provided by NLM:


Further study details as provided by Benjamin Bleier, Massachusetts Eye and Ear Infirmary:

Primary Outcome Measures:
  • Subjective Sinonasal Symptoms on Sinonasal Outcomes Test-22(SNOT-22) [ Time Frame: baseline to week 8 ]
    Minimun Score: 0 Maximum Score: 110 A higher score indicates a worse outcome

  • 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.


Secondary Outcome Measures:
  • 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.

  • Objective Sinonasal Symptoms on Lund-McKay Score(LMS) [ Time Frame: Week 8 ]
    Minimum Score: 0 Maximum Score: 24 Higher value represents worse outcome.


Other Outcome Measures:
  • Heart Rate [ Time Frame: Mean change between baseline and week 8 measurements. ]
  • Systolic Blood Pressure [ Time Frame: Mean change between baseline and week 8 measurements ]
  • Diastolic Blood Pressure [ Time Frame: Mean change between baseline and week 8 measurements ]

Enrollment: 20
Study Start Date: May 2015
Study Completion Date: March 2016
Primary Completion Date: March 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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.

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.

  Eligibility

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

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02454608

Locations
United States, Massachusetts
Massachusetts Eye and Ear Infirmary
Boston, Massachusetts, United States, 02114
Sponsors and Collaborators
Benjamin Bleier
Investigators
Principal Investigator: Benjamin S Bleier, MD Massachusetts Eye and Ear Infirmary
  More Information

Publications:

Responsible Party: Benjamin Bleier, Principal Investigator, Massachusetts Eye and Ear Infirmary
ClinicalTrials.gov Identifier: NCT02454608     History of Changes
Other Study ID Numbers: 15-009H
Study First Received: May 11, 2015
Results First Received: August 29, 2016
Last Updated: March 24, 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
Sinusitis
Nasal Polyps
Paranasal Sinus Diseases
Nose Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Otorhinolaryngologic Diseases
Polyps
Pathological Conditions, Anatomical
Verapamil
Anti-Arrhythmia Agents
Calcium Channel Blockers
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents

ClinicalTrials.gov processed this record on August 18, 2017