Trial of Topical Verapamil in Chronic Rhinosinusitis With Nasal Polyps

NCT03102190 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: 17-002H
• Study Type: interventional
• Target: 6
• Locations: 1 country
• Sites: 1

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.

Conditions

Sinusitis; Nasal Polyps

Outcome Measures

Primary Outcomes (1)

• 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

Study Arms (1)

Phase Ib

EXPERIMENTAL

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

Interventions

Verapamil Hydrochloride Intranasal DRUG

Verapamil solution for injection, supplied in vials, will be utilized in a Neil Med Sinus Rinse of 240mL buffered normal saline.

Phase Ib

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Benjamin Bleier: lead

Study Sites (1)

Massachusetts Eye and Ear

Boston, Massachusetts, 02114, United States

Location

Related Publications (12)

• 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. No abstract available.

  PMID: 28126245 BACKGROUND

• 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. doi: 10.1016/j.otohns.2004.10.010.

  PMID: 15692526 BACKGROUND

• 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.

  PMID: 23172039 BACKGROUND

• 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.

  PMID: 22887970 BACKGROUND

• 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.

  PMID: 22133887 BACKGROUND

• 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. doi: 10.1253/circj.cj-09-0467. Epub 2010 Jan 30.

  PMID: 20118567 BACKGROUND

• 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. doi: 10.1007/s00011-005-0060-y.

  PMID: 16673153 BACKGROUND

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

  PMID: 23773141 BACKGROUND

• 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.

  PMID: 21258839 BACKGROUND

• 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.

  PMID: 19793277 BACKGROUND

• 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.

  PMID: 22764607 BACKGROUND

• 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. doi: 10.1111/j.1398-9995.2005.00688.x.

  PMID: 15647046 BACKGROUND

MeSH Terms

Conditions

Sinusitis; Nasal Polyps

Condition Hierarchy (Ancestors)

Respiratory Tract Infections; Infections; Paranasal Sinus Diseases; Nose Diseases; Respiratory Tract Diseases; Otorhinolaryngologic Diseases; Polyps; Pathological Conditions, Anatomical; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Project Manager, Clinical Trials
• Organization: Massachusetts Eye and Ear Infirmary

elizabeth_grimm@meei.harvard.edu

617-573-6981

Study Officials

• Benjamin S Bleier, MD

  Massachusetts Eye and Ear

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 14, 2017
• First Posted: April 5, 2017
• Study Start: June 5, 2017
• Primary Completion: March 26, 2018
• Study Completion: March 26, 2018
• Last Updated: July 23, 2019
• Results First Posted: June 21, 2019

Record last verified: 2019-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)