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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

Tracking Information
First Submitted Date  ICMJE February 14, 2017
First Posted Date  ICMJE April 5, 2017
Results First Submitted Date  ICMJE March 26, 2019
Results First Posted Date  ICMJE June 21, 2019
Last Update Posted Date July 23, 2019
Actual Study Start Date  ICMJE June 5, 2017
Actual Primary Completion Date March 26, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 15, 2019)
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)
Original Primary Outcome Measures  ICMJE
 (submitted: March 30, 2017)
  • 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)
  • Sinonasal Outcomes Test (SNOT-22) [ Time Frame: 1-4 weeks ]
    The Sinonasal Outcomes Test is a validated 22 point symptom scale. It will be the primary outcome measure for Phase II.
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: March 30, 2017)
  • Intermediate toxicity as defined by cardiac effects [ Time Frame: 1-8 weeks ]
    Intermediate toxicity will be defined as: a heart rate of <50, an asymptomatic BP reduction >30% from baseline or SBP <90mmHg, an asymptomatic AMP reduction >30% from baseline or MAP<55, an asymptomatic DBP reduction >30% from baseline, and a Meltzer Compliance Grade >4 (Phase Ib Secondary Outcome I)
  • Mild toxicity as defined by Meltzer compliance grade [ Time Frame: 1-8 weeks ]
    Mild toxicity will be defined as a Meltzer Compliance Grade of 2-3. (Phase Ib Secondary Outcome II)
  • Lund-Kennedy Score (LKS) [ Time Frame: 1-4 weeks ]
    Lund-Kennedy Score is an objective measure of the pathologic state of the sinuses. (Phase II Secondary Outcome)
  • Subjective 10cm Visual Analog Scale [ Time Frame: 1-4 weeks ]
    The 10cm VAS is a subjective measure of overall symptom severity. (Phase II Secondary Outcome)
  • Meltzer Satisfaction and Compliance Scores [ Time Frame: 1-4 weeks ]
    The Meltzer Satisfaction and Compliance Scores are a subjective measure of satisfaction with the nasal irrigation. (Phase II Secondary Outcome)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: March 30, 2017)
Sinonasal Outcomes Test (SNOT-22) [ Time Frame: 1-8 weeks ]
A Phase Ib exploratory outcome will be to determine the efficacy of Verapamil HCl Intranasal using SNOT-22 scores.
 
Descriptive Information
Brief Title  ICMJE Trial of Topical Verapamil in Chronic Rhinosinusitis With Nasal Polyps
Official Title  ICMJE Phase Ib/II Clinical Trial of Topical Verapamil Hydrochloride for Chronic Rhinosinusitis With Nasal Polyps
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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Sinusitis
  • Nasal Polyps
Intervention  ICMJE 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.
Study Arms  ICMJE 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.
Intervention: Drug: Verapamil Hydrochloride Intranasal
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: March 26, 2019)
6
Original Estimated Enrollment  ICMJE
 (submitted: March 30, 2017)
40
Actual Study Completion Date  ICMJE March 26, 2018
Actual Primary Completion Date March 26, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
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 NCT03102190
Other Study ID Numbers  ICMJE 17-002H
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
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
PRS Account Massachusetts Eye and Ear Infirmary
Verification Date July 2019

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