Trial of Topical Verapamil in Chronic Rhinosinusitis With Nasal Polyps

Sinusitis Clinical Trial

Official title:

Phase Ib/II Clinical Trial of Topical Verapamil Hydrochloride for Chronic Rhinosinusitis With Nasal Polyps

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03102190
• Other study ID #: 17-002H
• Status: Terminated
• Phase: Phase 1
• Start date: June 5, 2017
• Est. completion date: March 26, 2018

Study information

• Verified date: July 2019
• Source: Massachusetts Eye and Ear Infirmary
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 6
• Est. completion date: March 26, 2018
• Est. primary completion date: March 26, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Nasal Polyps
• Polyps
• Sinusitis

Intervention

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.

Locations

Country	Name	City	State
United States	Massachusetts Eye and Ear	Boston	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Benjamin Bleier

Country where clinical trial is conducted

United States, 

References & Publications (12)

Becker WJ. Cluster headache: conventional pharmacological management. Headache. 2013 Jul-Aug;53(7):1191-6. doi: 10.1111/head.12145. Epub 2013 Jun 14. Review. — View Citation

Chin D, Harvey RJ. Nasal polyposis: an inflammatory condition requiring effective anti-inflammatory treatment. Curr Opin Otolaryngol Head Neck Surg. 2013 Feb;21(1):23-30. doi: 10.1097/MOO.0b013e32835bc3f9. Review. — View Citation

Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, Cohen N, Cervin A, Douglas R, Gevaert P, Georgalas C, Goossens H, Harvey R, Hellings P, Hopkins C, Jones N, Joos G, Kalogjera L, Kern B, Kowalski M, Price D, Riechelmann H, Schlosser R, Senior B, Thomas M, Toskala E, Voegels R, Wang de Y, Wormald PJ. European Position Paper on Rhinosinusitis and Nasal Polyps 2012. Rhinol Suppl. 2012 Mar;23:3 p preceding table of contents, 1-298. — View Citation

Hopkins C, Gillett S, Slack R, Lund VJ, Browne JP. Psychometric validity of the 22-item Sinonasal Outcome Test. Clin Otolaryngol. 2009 Oct;34(5):447-54. doi: 10.1111/j.1749-4486.2009.01995.x. — View Citation

Khakzad MR, Mirsadraee M, Mohammadpour A, Ghafarzadegan K, Hadi R, Saghari M, Meshkat M. Effect of verapamil on bronchial goblet cells of asthma: an experimental study on sensitized animals. Pulm Pharmacol Ther. 2012 Apr;25(2):163-8. doi: 10.1016/j.pupt.2011.11.001. Epub 2011 Nov 25. — View Citation

Klossek JM, Neukirch F, Pribil C, Jankowski R, Serrano E, Chanal I, El Hasnaoui A. Prevalence of nasal polyposis in France: a cross-sectional, case-control study. Allergy. 2005 Feb;60(2):233-7. — View Citation

Lanteri-Minet M, Silhol F, Piano V, Donnet A. Cardiac safety in cluster headache patients using the very high dose of verapamil (=720 mg/day). J Headache Pain. 2011 Apr;12(2):173-6. doi: 10.1007/s10194-010-0289-x. Epub 2011 Jan 22. — View Citation

Li G, Qi XP, Wu XY, Liu FK, Xu Z, Chen C, Yang XD, Sun Z, Li JS. Verapamil modulates LPS-induced cytokine production via inhibition of NF-kappa B activation in the liver. Inflamm Res. 2006 Mar;55(3):108-13. — View Citation

Matsumori A, Nishio R, Nose Y. Calcium channel blockers differentially modulate cytokine production by peripheral blood mononuclear cells. Circ J. 2010 Mar;74(3):567-71. Epub 2010 Jan 30. — View Citation

Meltzer EO, Hadley J, Blaiss M, Benninger M, Kimel M, Kleinman L, Dupclay L, Garcia J, Leahy M, Georges G. Development of questionnaires to measure patient preferences for intranasal corticosteroids in patients with allergic rhinitis. Otolaryngol Head Neck Surg. 2005 Feb;132(2):197-207. — View Citation

Miyake MM, Nocera A, Levesque P, Guo R, Finn CA, Goldfarb J, Gray S, Holbrook E, Busaba N, Dolci JEL, Bleier BS. Double-blind placebo-controlled randomized clinical trial of verapamil for chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2017 Jul;140(1):271-273. doi: 10.1016/j.jaci.2016.11.014. Epub 2017 Jan 23. — View Citation

Poetker DM, Jakubowski LA, Lal D, Hwang PH, Wright ED, Smith TL. Oral corticosteroids in the management of adult chronic rhinosinusitis with and without nasal polyps: an evidence-based review with recommendations. Int Forum Allergy Rhinol. 2013 Feb;3(2):104-20. doi: 10.1002/alr.21072. Epub 2012 Aug 7. Review. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Dose Limiting Toxicity	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)	1-8 weeks