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Trial of Verapamil in Chronic Rhinosinusitis

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ClinicalTrials.gov Identifier: NCT02454608
Recruitment Status : Terminated (Evidence that the dose is insufficient.)
First Posted : May 27, 2015
Results First Posted : December 28, 2016
Last Update Posted : June 14, 2018
Sponsor:
Information provided by (Responsible Party):
Benjamin Bleier, Massachusetts Eye and Ear Infirmary

Tracking Information
First Submitted Date  ICMJE May 11, 2015
First Posted Date  ICMJE May 27, 2015
Results First Submitted Date  ICMJE August 29, 2016
Results First Posted Date  ICMJE December 28, 2016
Last Update Posted Date June 14, 2018
Study Start Date  ICMJE May 2015
Actual Primary Completion Date March 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 16, 2018)
  • 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
  • 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.
  • 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
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: May 22, 2015)
  • Subjective Sinonasal Symptoms on Sinonasal Outcomes Test-22(SNOT-22) [ Time Frame: 8 weeks ]
    Validated outcome test to assess symptoms in chronic rhinosinusitis.
  • Subjective Sinonasal Symptoms on 10cm Visual Analogue Scale(VAS) [ Time Frame: 8 weeks ]
    Validated outcome test to assess symptoms in chronic rhinosinusitis.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 27, 2016)
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 22, 2015)
  • Objective Sinonasal Symptoms on Lund-Kennedy Score(LKS) [ Time Frame: 8 weeks ]
    Nasal endoscopy score validated to assess objective measures of chronic rhinosinusitis.
  • Objective Sinonasal Symptoms on Lund-McKay Score(LMS) [ Time Frame: 8 weeks ]
    Computed Tomography Inflammation Score validated to assess objective measures of chronic
Current Other Pre-specified Outcome Measures
 (submitted: October 27, 2016)
  • 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 ]
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Trial of Verapamil in Chronic Rhinosinusitis
Official Title  ICMJE Randomized Double Blind Placebo Controlled Trial of Verapamil in Chronic Rhinosinusitis
Brief Summary 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.
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  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Sinusitis
  • Nasal Polyps
Intervention  ICMJE
  • 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 Name: Verapamil
  • Other: Placebo
    Capsule with the same characteristics (size, color, smell) as Verapamil HCl.
Study Arms  ICMJE
  • Experimental: Treatment
    Verapamil HCl, capsules for oral administration, 80mg, TID, for 8 weeks
    Intervention: Drug: Verapamil HCl
  • Placebo Comparator: Control
    Placebo, capsules for oral administration, TID, for 8 weeks
    Intervention: Other: Placebo
  • Experimental: Open Label
    Verapamil HCl, capsules for oral administration, 80mg, TID, for 1 year
    Intervention: Drug: Verapamil HCl
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: May 16, 2018)
29
Original Estimated Enrollment  ICMJE
 (submitted: May 22, 2015)
158
Actual Study Completion Date  ICMJE May 2017
Actual Primary Completion Date March 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02454608
Other Study ID Numbers  ICMJE 15-009H
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Benjamin Bleier, Massachusetts Eye and Ear Infirmary
Study Sponsor  ICMJE Benjamin Bleier
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Benjamin S Bleier, MD Massachusetts Eye and Ear Infirmary
PRS Account Massachusetts Eye and Ear Infirmary
Verification Date May 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP