Trial of Verapamil in Chronic Rhinosinusitis

Sinusitis Clinical Trial

Official title:

Randomized Double Blind Placebo Controlled Trial of Verapamil in Chronic Rhinosinusitis

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02454608
• Other study ID #: 15-009H
• Status: Terminated
• Phase: N/A
• Start date: May 2015
• Est. completion date: May 2017

Study information

• Verified date: May 2018
• 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. 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 29
• Est. completion date: May 2017
• Est. primary completion date: March 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Nasal Polyps
• Sinusitis

Intervention

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:
• Placebo
Capsule with the same characteristics (size, color, smell) as Verapamil HCl.

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Benjamin Bleier

Country where clinical trial is conducted

United States, 

References & Publications (12)

Bacon KB, Westwick J, Camp RD. Potent and specific inhibition of IL-8-, IL-1 alpha- and IL-1 beta-induced in vitro human lymphocyte migration by calcium channel antagonists. Biochem Biophys Res Commun. 1989 Nov 30;165(1):349-54. — View Citation

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

Cohen AS, Matharu MS, Goadsby PJ. Electrocardiographic abnormalities in patients with cluster headache on verapamil therapy. Neurology. 2007 Aug 14;69(7):668-75. — 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

Hashioka S, Klegeris A, McGeer PL. Inhibition of human astrocyte and microglia neurotoxicity by calcium channel blockers. Neuropharmacology. 2012 Sep;63(4):685-91. doi: 10.1016/j.neuropharm.2012.05.033. Epub 2012 May 30. — 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

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

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
Other	Heart Rate		Mean change between baseline and week 8 measurements.
Other	Systolic Blood Pressure		Mean change between baseline and week 8 measurements
Other	Diastolic Blood Pressure		Mean change between baseline and week 8 measurements
Primary	Subjective Sinonasal Symptoms on Sinonasal Outcomes Test-22(SNOT-22)	Minimum Score: 0 Maximum Score: 110 A higher score indicates a worse outcome	baseline to week 8
Primary	Subjective Sinonasal Symptoms on 10cm Visual Analogue Scale(VAS)	Minimum Score: 0 Maximum Score: 100 A higher score indicates a worse outcome.	baseline to week 8
Primary	Subjective Sinonasal Symptoms on Sinonasal Outcomes Test-22(SNOT-22)	Minimum Score: 0 Maximum Score: 110 A higher score indicates a worse outcome	baseline to week 56
Primary	Subjective Sinonasal Symptoms on 10cm Visual Analogue Scale(VAS)	Minimum Score: 0 Maximum Score: 100 A higher score indicates a worse outcome.	baseline to week 56
Secondary	Objective Sinonasal Symptoms on Lund-Kennedy Score(LKS)	Minimum Score: 0 Maximum Score: 12 Higher value represents worse outcome.	baseline to week 8
Secondary	Objective Sinonasal Symptoms on Lund-McKay Score(LMS)	Minimum Score: 0 Maximum Score: 24 Higher value represents worse outcome.	Week 8