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Trial of Topical Verapamil in Chronic Rhinosinusitis With Nasal Polyps

This study is currently recruiting participants.
See Contacts and Locations
Verified June 2017 by Benjamin Bleier, Massachusetts Eye and Ear Infirmary
Sponsor:
Information provided by (Responsible Party):
Benjamin Bleier, Massachusetts Eye and Ear Infirmary
ClinicalTrials.gov Identifier:
NCT03102190
First received: February 14, 2017
Last updated: June 7, 2017
Last verified: June 2017
  Purpose
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.

Condition Intervention Phase
Sinusitis Nasal Polyps Drug: Verapamil Hydrochloride Intranasal Phase 1 Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: Phase Ib/II Clinical Trial of Topical Verapamil Hydrochloride for Chronic Rhinosinusitis With Nasal Polyps

Resource links provided by NLM:


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

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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)


Other Outcome Measures:
  • 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.


Estimated Enrollment: 40
Actual Study Start Date: June 5, 2017
Estimated Study Completion Date: July 2019
Estimated Primary Completion Date: May 2019 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Experimental: Phase II
The Phase II study will be an open label safety and efficacy expansion cohort using the Verapamil Hydrochloride Intranasal MTD determined in the Phase IB arm. A total of 20 patients will be administered the MTD of topical Verapamil HCl in a 240mL buffered normal nasal rinse for 4 weeks BID. Patients will then return for follow-up visits at 1 week and 4 weeks. Subjective and objective outcome measures will be collected at each visit
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.

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.

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years   (Adult, Senior)
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.
  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: NCT03102190

Contacts
Contact: Patricia Levesque 617-573-3576 patricia_levesque@meei.harvard.edu

Locations
United States, Massachusetts
Massachusetts Eye and Ear Recruiting
Boston, Massachusetts, United States, 02114
Contact: Patricia Levesque    617-573-3576    patricia_levesque@meei.harvard.edu   
Principal Investigator: Benjamin S Bleier, MD         
Sponsors and Collaborators
Benjamin Bleier
Investigators
Principal Investigator: Benjamin S Bleier, MD Massachusetts Eye and Ear
  More Information

Publications:

Responsible Party: Benjamin Bleier, Principal Investigator, Massachusetts Eye and Ear Infirmary
ClinicalTrials.gov Identifier: NCT03102190     History of Changes
Other Study ID Numbers: 17-002H
Study First Received: February 14, 2017
Last Updated: June 7, 2017
Individual Participant Data  
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Polyps
Sinusitis
Nasal 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
Vasodilator Agents

ClinicalTrials.gov processed this record on June 23, 2017