Conditions: Sinusitis Nasal Polyps
Allocation:  | Intervention model: SEQUENTIAL
Enrollment: 6
Healthy volunteers: no

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.

Arms:
arm 1: 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.

Interventions: intervention 1: Verapamil Hydrochloride Intranasal
Intervention descriptions: intervention 1: Verapamil solution for injection, supplied in vials, will be utilized in a Neil Med Sinus Rinse of 240mL buffered normal saline.

Protocol document:
Prot_SAP_000.pdf: 
Phase Ib/II Clinical Trial of Topical Verapamil HCl for 
Chronic Rhinosinusitis with Nasal Polyps 
Protocol Identifying Number: 17-002H 
Principal Investigator: Benjamin Bleier, MD 
IND/IDE Sponsor: N/a 
Funded by:  
Draft or Version Number:  2.31 
06 June 2017 
 


ii 
 
Table of Contents 
LIST OF ABBREVIATIONS ................................................................................................................................ 1 
STATEMENT OF COMPLIANCE ....................................................................................................................... 2 
PROTOCOL SUMMARY ..................................................................................................................................... 2 
SCHEMATIC OF STUDY DESIGN .................................................................................................................... 3 
1 
KEY ROLES ............................................................................................................................................. 4 
2  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ....................... 4 
2.1 
Background Information ................................................................................................................ 4 
2.2 
Rationale ........................................................................................................................................ 4 
2.3 
Potential Risks and Benefits ......................................................................................................... 6 
2.3.1 
Known Potential Risks ................................................................................................ 7 
2.3.2 
Known Potential Benefits ........................................................................................... 8 
3 
OBJECTIVES AND PURPOSE .............................................................................................................. 8 
4 
STUDY DESIGN AND ENDPOINTS ...................................................................................................... 8 
4.1 
Description of the Study Design ................................................................................................... 8 
4.2.1 
Primary Endpoint ........................................................................................................ 9 
4.2.2 
Secondary Endpoints ................................................................................................. 9 
4.2.3 
Exploratory Endpoints .............................................................................................. 10 
5 
STUDY ENROLLMENT AND WITHDRAWAL ..................................................................................... 10 
5.1 
Participant Inclusion Criteria ....................................................................................................... 10 
5.2 
Participant Exclusion Criteria ...................................................................................................... 10 
5.3 
Strategies for Recruitment and Retention ................................................................................. 10 
5.4 
Participant Withdrawal or termination ........................................................................................ 12 
5.4.1 
Reasons for Withdrawal or Termination .................................................................. 12 
5.4.2 
Handling of Participant Withdrawals or termination ............................................... 12 
5.5 
Premature Termination or Suspension of Study ....................................................................... 13 
6 
STUDY AGENT ..................................................................................................................................... 13 
6.1 
Study Agent(s) and Control Description .................................................................................... 13 
6.1.1 
Acquisition ................................................................................................................. 13 
6.1.2 
Formulation, Appearance, Packaging, and Labeling ............................................. 13 
6.1.3 
Product Storage and Stability .................................................................................. 13 
6.1.4 
Preparation ................................................................................................................ 14 
6.1.5 
Dosing and Administration ....................................................................................... 14 
6.1.6 
Route of Administration ............................................................................................ 14 
6.1.7 
Starting Dose and Dose Escalation Schedule ........................................................ 15 
6.1.8 
Dose Adjustments/Modifications/Delays ................................................................. 15 
6.1.9 
Duration of Therapy .................................................................................................. 15 
6.1.10 
Tracking of Dose ....................................................................................................... 15 
6.1.11 
Device Specific Considerations ............................................................................... 15 
6.2 
Study agent Accountability Procedures ..................................................................................... 15 
7 
STUDY PROCEDURES AND SCHEDULE ......................................................................................... 15 
7.1 
Study Procedures/Evaluations ................................................................................................... 15 
7.1.1 
Study specific procedures ........................................................................................ 15 
7.1.2 
Standard of care study procedures ......................................................................... 16 
7.2 
Laboratory Procedures/Evaluations ........................................................................................... 16 
7.2.1 
Clinical Laboratory Evaluations ............................................................................... 16 


iii 
 
7.2.2 
Other Assays or Procedures .................................................................................... 16 
7.2.3 
Specimen Preparation, Handling, and Storage ...................................................... 17 
7.2.4 
Specimen Shipment ................................................................................................. 18 
7.3 
Study Schedule............................................................................................................................ 18 
7.3.1 
Screening .................................................................................................................. 18 
7.3.2 
Enrollment/Baseline .................................................................................................. 18 
7.3.3 
Follow-up ................................................................................................................... 19 
7.3.4 
Final Study Visit ........................................................................................................ 19 
7.3.5 
Early Termination Visit ............................................................................................. 19 
7.3.7 
Schedule of Events Table ........................................................................................ 20 
7.4 
Justification for Sensitive Procedures ........................................................................................ 20 
7.5 
Concomitant Medications, Treatments, and Procedures ......................................................... 20 
7.5.1 
Precautionary Medications, Treatments, and Procedures ..................................... 20 
7.6 
Prohibited Medications, Treatments, and Procedures .............................................................. 20 
7.7 
Prophylactic Medications, Treatments, and Procedures .......................................................... 20 
7.8 
Rescue Medications, Treatments, and Procedures .................................................................. 20 
7.9 
Participant Access to Study Agent At Study Closure................................................................ 21 
8 
ASSESSMENT OF SAFETY ................................................................................................................ 21 
8.1 
Specification of Safety Parameters ............................................................................................ 21 
8.1.1 
Definition of Adverse Events (AE) ........................................................................... 21 
8.1.2 
Definition of Serious Adverse Events (SAE) ........................................................... 21 
8.1.3 
Definition of Unanticipated Problems (UP) ............................................................. 21 
8.2 
Classification of an Adverse Event ............................................................................................. 22 
8.2.1 
Severity of Event ....................................................................................................... 22 
8.2.2 
Relationship to Study Agent ..................................................................................... 22 
8.2.3 
Expectedness............................................................................................................ 22 
8.3 
Time Period and Frequency for Event Assessment and Follow-Up ........................................ 23 
8.4 
Reporting Procedures ................................................................................................................. 23 
8.4.1 
Adverse Event Reporting ......................................................................................... 23 
8.4.2 
Serious Adverse Event Reporting ........................................................................... 23 
8.4.3 
Unanticipated Problem Reporting............................................................................ 24 
8.4.4 
Events of Special Interest ........................................................................................ 24 
8.4.5 
Reporting of Pregnancy............................................................................................ 24 
8.5 
Study Halting Rules ..................................................................................................................... 24 
8.6 
Safety Oversight .......................................................................................................................... 24 
9 
CLINICAL MONITORING ...................................................................................................................... 24 
10 
STATISTICAL CONSIDERATIONS ..................................................................................................... 25 
10.1 
Statistical and Analytical Plans ................................................................................................... 25 
10.2 
Statistical Hypotheses ................................................................................................................. 25 
10.3 
Analysis Datasets ........................................................................................................................ 25 
10.4 
Description of Statistical Methods .............................................................................................. 26 
10.4.1 
General Approach ..................................................................................................... 26 
10.4.2 
Analysis of the Primary Efficacy Endpoint(s) .......................................................... 26 
10.4.3 
Analysis of the Secondary Endpoint(s) ................................................................... 26 
10.4.4 
Safety Analyses ........................................................................................................ 26 
10.4.5 
Adherence and Retention Analyses ........................................................................ 26 


iv 
 
10.4.6  
Baseline Descriptive Statistics ................................................................................. 26 
10.4.7 
Planned Interim Analyses ........................................................................................ 27 
10.4.9 
Multiple Comparison/Multiplicity .............................................................................. 27 
10.4.10 
Tabulation of Individual Response Data ................................................................. 27 
10.4.11 
Exploratory Analyses ................................................................................................ 27 
10.5 
Sample Size ................................................................................................................................. 27 
10.6 
Measures to Minimize Bias ......................................................................................................... 28 
10.6.1 
Enrollment/ Randomization/ Masking Procedures ................................................. 28 
10.6.2 
Evaluation of Success of Blinding ........................................................................... 28 
10.6.3 
Breaking the Study Blind/Participant Code ............................................................. 28 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ................................. 28 
12 
QUALITY ASSURANCE AND QUALITY CONTROL .......................................................................... 28 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS............................................................................... 28 
13.1 
Ethical Standard .......................................................................................................................... 29 
13.2 
Institutional Review Board .......................................................................................................... 29 
13.3 
Informed Consent Process ......................................................................................................... 29 
13.3.1 
Consent/assent and Other Informational Documents Provided to Participants ... 29 
13.3.2 
Consent Procedures and Documentation ............................................................... 29 
13.4 
Participant and data Confidentiality............................................................................................ 29 
13.4.1 
Research Use of Stored Human Samples,Specimens or Data ............................. 30 
13.5 
Future Use of Stored Specimens ............................................................................................... 30 
14 
DATA HANDLING AND RECORD KEEPING ..................................................................................... 30 
14.1 
Data Collection and Management Responsibilities................................................................... 30 
14.2 
Study Records Retention ............................................................................................................ 30 
14.3 
Protocol Deviations ..................................................................................................................... 31 
14.4 
Publication and Data Sharing Policy .......................................................................................... 31 
15 
STUDY ADMINISTRATION .................................................................................................................. 32 
15.1 
Study Leadership ......................................................................................................................... 32 
16 
CONFLICT OF INTEREST POLICY .................................................................................................... 32 
17  
LITERATURE REFERENCES .............................................................................................................. 32 
APPENDIX ......................................................................................................................................................... 36 
 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
BID 
Twice a day 
BMI  
Body Mass Index 
BP 
Blood Pressure 
CRF 
Case Report Form 
CRS 
Chronic Rhinosinusitis 
DLT 
Dose Limiting Toxicity 
DSMB 
Data and Safety Monitoring Board 
EKG 
Electrocardiogram 
ELISA 
Enzyme Linked Immunosorbent Assay 
FDA 
Food and Drug Administration 
GAPDH 
Glyceraldehyde-3-Phosphate Dehydrogenase 
GCP 
Good Clinical Practice 
HCl 
Hydrochloride 
IHC 
Immunohistochemistry 
IL 
Interleukin 
IN 
Intranasal 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ICC 
Intraclass Correlation Coefficient 
IT 
Intermediate Toxicity 
LMK 
Lund-Mackay 
LKS 
Lund-Kennedy Score 
LSM 
Least Squares Mean 
MAD 
 Maximal Administered Dose 
MAP 
Mean Arterial Pressure 
MCID 
Minimally Clinically Important Difference 
MEEI  
Massachusetts Eye and Ear Infirmary 
MTD 
Maximal Tolerated Dose 
PBS 
Phosphate Buffered Saline 
PCFD 
Partition Coefficient of the Free Drug 
P-gp 
P-glycoprotein 
PI 
Principle Investigator 
PVA 
Polyvinyl Alcohol Sponge 
SA 
Specific Aims 
SNOT-22 
Sinonasal Outcomes Test (22-item) 
sNP 
Without Nasal Polyps 
SEB 
Staphylococcal aureus enterotoxin B 
TEM 
Transmission Electron Microscopy 
Th2 
Type 2 Helper T-cell 
TID 
Three Times a Day 
TSLP 
Thymic Stromal Lymphoprotein 
UCF 
Ultracentrifugation 
wNP 
With Nasal Polyps 
VAS 
Visual Analog Scale 
Zos 
Zosuquidar Trihydrochloride 
 


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STATEMENT OF COMPLIANCE 
This trial will be conducted in accordance with the ICH E6, the Code of Federal Regulations on the 
Protection of Human Subjects (45 CFR Part 46), and the <NIH IC> Terms of Award. The Principal 
Investigator will assure that no deviation from, or changes to the protocol will take place without prior 
agreement from the sponsor and documented approval from the Institutional Review Board (IRB), 
except where necessary to eliminate an immediate hazard(s) to the trial participants. All personnel 
involved in the conduct of this study have completed Human Subjects Protection Training. 
 
I agree to ensure that all staff members involved in the conduct of this study are informed about their 
obligations in meeting the above commitments.  
Principal Investigator: ________________________________ 
Print/Type Name  
Signed: _____________________________________ Date: ______________ 
 
PROTOCOL SUMMARY 
Title: 
Phase Ib/II Clinical Trial of Topical Verapamil HCl for Chronic Rhinosinusitis with Nasal 
Polyps 
Précis: 
Phase Ib will be an accelerated titration, intrapatient dose escalation cohort, with double-
dose step design. Participants will administer each dose Verapamil HCl dose intranasally BID. 
Weekly visits will occur for side-effect and escalation evaluations. Phase II will be an open label 
trial of 20 participants. The MTD determined in Phase Ib will be administered BID for 4 weeks. 
Participants will be seen at baseline, 1 week, and 4 week for efficacy and side-effect 
evaluations. 
Objectives: 
 
Primary Objectives: 
-Perform a Phase IB trial of topical intranasal Verapamil HCl BID to determine the Maximal 
Tolerated Dose(MTD) using an accelerated titration design with intra-patient dose escalation. 
-Perform a Phase II trial of topical intranasal Verapamil HCl BID based on the Phase I MTD to 
determine safety and efficacy using both subjective and objective outcome measures of CRS. 
Secondary Objective: 
-Determine whether mucus derived exosomal P-gp can be used as a non-invasive biomarker of 
CRS by correlating it with baseline symptoms of CRSwNP and treatment response to topical 
Verapamil HCl at the MTD.  
Endpoint 
Primary Endpoints: 
Phase Ib: Defining the Maximal Tolerated Dose(MTD) of topical Verapamil HCl. DLT will be 
defined as a development of 2nd or 3rd degree heart block as measured by an EKG. 
Phase II: determining the efficacy of topical Verapamil HCl at the MTD for subjective symptoms 
of CRSwNP using the validated SNOT-22. 
Secondary Endpoints: 
Phase Ib: 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. 


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Phase II: to determine the efficacy of Verapamil HCl at the MTD as measured by a subjective 
10cm visual analog scale(VAS), Meltzer topical irrigation satisfaction and compliance scores, 
and the validated Lund-Kennedy nasal endoscopy score(LKS). 
Population: 
20-40 MEE Sinus Center patients over the age of 18 who present with chronic 
rhinosinusitis with polyps.  
Phase: 
IB/II 
Number of 
Sites 
enrolling 
participants: 
1 
Description 
of Study 
Agent : 
Verapamil HCl 0.3mg-3.6mg final dose BID in buffered normal saline as a nasal 
irrigation.  
Study 
Duration: 
December 2016 – December 2018 
Participant 
Duration: 
1 month 
SCHEMATIC OF STUDY DESIGN 
 


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1 
KEY ROLES 
Name, degree 
Institution 
Address 
Phone Number 
Email 
Benjamin Bleier, 
MD 
MEEI 
243 Charles St, 
Boston, MA 02114 
617-573-6966 
Benjamin_Bleier@meei.harvard.edu 
Patricia 
Levesque, BS 
MEEI 
243 Charles St, 
Boston, MA 02114 
617-573-3576 
Patricia_levesque@meei.harvard.edu 
Sarina Mueller, 
MD 
MEEI 
243 Charles St, 
Boston, MA 02114 
n/a 
Sarina_mueller@meei.harvard.edu 
Jeremy 
Goldfarb, MD 
MEEI 
243 Charles St, 
Boston, MA 02114 
617-573-3380 
Jeremy_goldfarb@meei.harvard.edu 
Christine Finn, 
Pharm-D 
MEEI 
243 Charles St, 
Boston, MA 02114 
617-573-3315 
Christine_finn@meei.harvard.edu 
Angela Nocera, 
MS 
MEEI 
243 Charles St, 
Boston, MA 02114 
n/a 
Alnocera5@gmail.com 
Hang Lee, Ph.D.  MGH Biostatistics 
Center 
50 Staniford St, 
Boston, MA 02114 
617-726-4293 
Hlee5@mgh.harvard.edu 
 
2  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
 
2.1 BACKGROUND INFORMATION  
P-glycoprotein is overexpressed in Th2 polarized endotypes of CRS and correlates with indices of disease 
severity. Previous studies by our group have demonstrated that P-gp is differentially overexpressed in the sinus 
mucosa of patients with CRSwNP relative to CRS without Nasal Polyp(CRSsNP) and control patients. This 
overexpression is specific to the sinus mucosa as the adjacent non-polypoid septum has similar expression levels 
across all patient groups [10]. We next focused on the CRSsNP population to determine whether P-gp expression 
correlated with clinical severity. We found that high P-gp expression patients with CRS had greater tissue 
eosinophilia and worse CT inflammatory scores than their low P-gp expression CRSsNP counterparts. These 
findings indicate that P-gp is overexpressed in CRSwNP and eosinophilic CRSsNP, both of which are associated with 
Th2 polarized inflammation.  
P-gp overexpression in CRSwNP directly leads to Th2 cytokine hyper-secretion. Having demonstrated that P-
gp is overexpressed in Th2 polarized forms of CRS(CRSwNP and eosinophilic CRSsNP), we next studied whether this 
overexpression is associated with increased secretion of cytokines which promote Th2 inflammatory pathways. We 
utilized an organotypic explant model to confirm that P-gp is overexpressed in CRSwNP relative to non-eosinophilic 
CRSsNP. Using this explant model we showed that P-gp directly promotes the secretion of both IL-5 and thymic 
stromal lymphopoietin (TSLP). Furthermore, the degree of secretion of these important Th2 polarizing cytokines 
was strongly and significantly correlated with P-gp expression within the same explant[45]. These results confirm 
previous in vitro findings by our group in polyp derived epithelial cell cultures[44]. Taken together, these results 
demonstrate that P-gp mediated cytokine hyper-secretion plays a critical role in the pathogenesis of Th2 polarized 
forms of CRS including CRSwNP.   


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Mucus derived exosomal P-gp is a non-invasive biomarker of CRSwNP. Our group recently reported on the 
presence of a secreted form of P-gp which could be detected in nasal mucus. While the presence of P-gp in mucus 
is physiologic, we showed that total P-gp concentrations above 250 pcg/μg of total protein are associated with 
CRSwNP as well as more severe subjective and objective findings of disease[13]. We subsequently discovered that 
this secretion was mediated by the release of exosomes which are differentially enriched with P-gp among patients 
with CRSwNP. In light of the importance of P-gp overexpression to the pathogenesis of CRSwNP, the development 
of a non-invasive test of expression which intrinsically resists degradation and can be correlated with disease 
severity would be extremely valuable.  
Verapamil HCl is an effective P-gp inhibitory therapy for CRSwNP. However well tolerated oral doses are 
subtherapeutic in patients with elevated BMI. The significant contribution of P-gp to the pathogenesis of CRSwNP 
suggests that it may represent a novel druggable target. We 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[14], for the treatment of CRSwNP[19]. While Verapamil is cardioactive, it is considered a first-line 
prophylactic drug for cluster headache and is well tolerated at 80mg three times a day(TID) by otherwise healthy 
patients[51]. Our findings demonstrated significant efficacy in both our 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 
SNOT-22(p=0.01). This is consistent with our use of a low dose of a relatively low potency inhibitor. The second is 
that patients with the highest total mucus P-gp levels experienced less benefit(p=0.01). This strongly suggests that 
the mechanism of Verapamil is acting through P-gp inhibition and that patients with greater expression may need 
higher concentrations to achieve adequate pump suppression. 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. 
Pharmacokinetic comparison of oral versus topical Verapamil administration. The bioavailability factor of 
Verapamil HCl has been estimated at 29-47.8% intranasal(IN) and 20-35% orally[52][53]. Due to the stereoselective 
first-pass effect of oral Verapamil, the dextro/levo isomer ratio should be taken into account indicating that 2-3 
times higher Verapamil concentrations are needed to obtain a similar effect after oral versus IN administration 
[54]. The ratio of the IN/oral bioavailability divided by the stereoselective effect suggests that an IN dose of 11.2-
48.5mg of Verapamil would be equivalent to a single 80mg oral dose. To achieve the same exposure effect at 
steady state TID dosing, the equivalent BID IN dose would therefore be 16.8-72.75mg. The partition coefficient of 
the free drug(PCFD), the unbound fraction capable of diffusing into the mucosa, has been estimated to be between 
2.0-8.0[55][56][57]. Based on the mucosal volumetric analysis by Sarangapani et al[58], the PCFD of Verapamil, and 


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our previous ¬in vitro data[48], the minimal peak IN dose required to achieve an adequate suppression of P-gp by 
Verapamil would be 0.03mg.  
2.2 RATIONALE  
Treatment of CRSwNP poses a significant challenge as the mechanisms responsible for initiating and 
maintaining Th2 inflammation are poorly understood. Consequently, the development of cost effective, targeted 
therapies, with limited off target toxicity remains a significant unmet need. This knowledge gap has also hindered 
the discovery and validation of novel biomarkers which could be used to predict disease endotype and prognosis. 
This proposal is based on several recent discoveries suggesting that P-glycoprotein(P-gp) functions as a key 
immunomodulator of Th2 cytokine secretion in CRSwNP. The P-gp hypothesis of CRSwNP has yielded both a novel 
druggable target as well as a possible non-invasive biomarker of disease severity and treatment response. The 
successful completion of this proposal therefore has the potential to significantly shift the way we diagnose and 
treat CRSwNP.  
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[20] [21].  CRS alone impacts more than 30 million Americans resulting in $6.9 to $9.9 billion in annual 
healthcare expenditures [22,23] and $12.8 billion in productivity costs[24]. The subset of patients in Europe with 
CRSwNP has been estimated to be between 2 and 4.3% [25][26][27] and is thought to be similar in the US. This 
population remains one of the most challenging subgroups of CRS to manage effectively. 
There is a significant lack of innovative therapeutic strategies in CRSwNP. This is due, in large part, to a lack 
of clear understanding of the pathways involved in the initiation and maintainance of the inflammation 
characteristic of the disease. While corticosteroids remain the best studied and most effective 
treatment[28][29][30][31], they are non-targeted and are therefore associated with significant off target effects. 
Even when applied topically, steroids may be absorbed systemically[2] and their efficacy has been questioned in 
several clinical trials[32][33]. Currently, the largest body of literature exploring the pathogenesis of CRSwNP has 
focused on Th2 polarizing inflammation as a key feature of the disease process[34][35]. This has catalyzed the 
exploration of monoclonal antibody therapies which target specific Th2 promoting cytokines in CRS with variable 
clinical success.  
Biologic therapies have had mixed results and are associated with significant drawbacks. Two anti-
Interleukin(IL)-5 agents Reslizumab[36] and Mepolizumab[37] have been studied in the context of CRSwNP. While 
improvement was demonstrated among certain objective signs of inflammation, patient symptoms scores failed to 
significantly improve. Dupilumab, a fully human monoclonal antibody to the IL-4 receptor α subunit that inhibits 
both IL-4 and IL-13 signaling has also recently been studied[38] [3]. The most recent study compared patients with 


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CRSwNP treated with placebo to Dupilumab for 16 weeks. This study demonstrated a significant improvement in 
SNOT-22 of −18.1 in the Dupilumab group however significant treatment related side effects were reported 
including a 47% rate of nasopharyngitis and 40% rate of injection site reactions. While the outcomes are promising, 
the need for weekly injections, significant side effects, high cost, and potential for loss of efficacy over time suggest 
that the development of alternative, cost effective, targeted non-steroidal therapeutic strategies are still needed 
to optimize treatment of CRSwNP. 
There is an unmet need for the discovery and validation of non-invasive biomarkers of CRSwNP. As 
personalized treatment of CRS continues to advance, the development of biomarkers of disease and endotype will 
become critical. A recent study by Tomassen et al[39] provided a proof of concept that an unsupervised partition 
based cluster analysis of tissue derived cytokines and inflammatory proteins could yield discreet clusters which 
correlated well with phenotypic characteristics. Despite the promise of this technique, the biomarkers studied 
required tissue sampling which was invasive, introduced the possibility of inter-patient heterogeneity in tissue 
composition, and protein degradation during the sampling and storage process. Furthermore, the inevitable 
medical therapies leading up to the surgical event at which the sampling occurred were not accounted for in the 
analysis. Consequently, a novel method of biomarker sampling which can be performed non-invasively in the 
outpatient setting prior to the initiation of medical therapy is needed. Ideally these biomarkers would directly 
participate in, and thereby closely reflect, the underlying pathophysiology and would be intrinsically resistant to 
degradation.  
Mucus derived exosomes represent an ideal potential biomarker reservoir. Exosomes are 30–150 nm 
vesicles surrounded by a lipid bilayer that are released from epithelial cells into nasal mucus[40][41] [42]. 
Biophysically, exosomes are equivalent to cytoplasm and carry integral membrane proteins, mRNA, and regulatory 
microRNA reflective of their cell of origin.  Studies have demonstrated that exosomes are able to shuttle their 
cargo to adjacent cells where they can exert a paracrine regulatory function on the recipient cell[43]. The tightly 
regulated composition of exosomes, their presence in nasal mucus, and their protective lipid bilayer make them a 
potentially ideal source of biomarkers for outpatient sampling which could out-perform total dissolved protein 
levels given their vulnerability to proteolytic degradation.  
The discovery of a new pathogenic mechanism for CRSwNP which yields both novel targeted therapeutics 
and non-invasive biomarkers of disease would represent an important and significant advance in the field of 
Rhinology.  
2.3 
POTENTIAL RISKS AND BENEFITS  
 
2.3.1 KNOWN POTENTIAL RISKS  


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Verapamil HCl is a cardioactive drug and thus there is a theoretical risk of cardiac side effects from the medication. 
This will be mitigated by obtaining a EKG which will be reviewed by a medical internist/anesthesiologist prior to 
initiating therapy. Follow-up EKGs will also be performed to monitor for cardiac side effects. The risk of cardiac 
effects appears to be dose-dependant and is expected to be mostly reversible upon discontinuation of the drug. 
Additional risks include bradycardia and hypotension. These will be mitigated by checking routine vital signs at 
each visit which will include heart rate and blood pressure. Constipation is also a risk of the drug. This will be asked 
about at each visit and stool softeners and/or laxatives will be administered as necessary. Since verapamil will be 
administered with a nasal rinse there is a possibility of nasal irritation. These side effects will be monitored at each 
study visit. 
There are currently few medical interventions available for CRSwNP. The development of new medications is 
critical to the management of this disease. Thus, the short-term risks for the trial patients will ultimately decrease 
the risks and discomforts that the overall CRSwNP population experiences. 
2.3.2 KNOWN POTENTIAL BENEFITS  
If successful, using Topical Verapamil will help treat pateints with CRSwNP and potentially enable them to avoid 
sinus surgery or steroid therapy with their attendant risks.  
Successful performance of Topical Verapamil will establish this drug as a novel therapeutic option for the 
treatment of CRSwNP as well as elucidate a mechanism of the pathophysiology of CRSwNP. This may also open 
avenues for the use of a new class of treatments for CRSwNP which work along the same mechanism. 
3 
OBJECTIVES AND PURPOSE 
Primary Objectives:  
- 
Perform a Phase IB trial of topical intranasal Verapamil HCl BID to determine the Maximal Tolerated 
Dose(MTD) using an accelerated titration design with intra-patient dose escalation. 
- 
Perform a Phase II trial of topical intranasal Verapamil HCl BID based on the MTD to determine safety and 
efficacy using both subjective and objective outcome measures of CRS. 
Secondary Objective: 
- 
Determine whether mucus derived exosomal P-gp can be used as a non-invasive biomarker of CRS by 
correlating it with baseline symptoms of CRSwNP and treatment response to topical Verapamil HCl at the 
MTD.  
4 
STUDY DESIGN AND ENDPOINTS 
 
4.1 
DESCRIPTION OF THE STUDY DESIGN 
ARM 1: Phase 1B 
The phase IB study will consist of an accelerated titration, intrapatient dose escalation cohort, with double-dose 
step design. The initial single patient cohort will begin by taking 0.3mg (10mg of Verapamil in 240mL of buffered 
normal saline yielding an established 3% residual nasal dose) as a nasal irrigation BID for 1 week. The first dose f 


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each escalation will be administered in a 10th or 11th floor MEE clinic withhemodynamic monitoring. A medically 
trained member of the study staff with monitor the patient for one hour.  Patients will be instructed on the how to 
properly perform the irrigation using a pre-recorded video demonstration. If no first-course dose limiting toxicity 
(DLT, defined by the development of 2nd or 3rd degree heart block) is noted then patients will continue taking the 
current Verapamil rinse dose BID for 1 week.  Dose escalation will occur weekly in the absence of a single, any 
course, DLT or a second, any course, intermediate toxicity(IT, defined by a heart rate of <50, an asymptomatic BP 
reduction >30% from baseline or systolic BP <90mmHg, an asymptomatic MAP reduction >30% from baseline or 
MAP<55, an asymptomatic diastolic BP reduction >30% from baseline, and a Meltzer Compliance Grade >4[60]). 
Each escalation will be a doubling of the dose from 0.3-2.4mg. At that point that dose will escalate in 0.6mg 
residual intervals for the rest of the trial up to a maximum of 3.6mg total residual dose. These doses were derived 
from the pharmacokinetic analysis of our oral Verapamil trial results.  If a single, any course, 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 preceeding dose.  
At each weekly visit, the patients nasal endoscopy will be recorded for LKS grading, and they will be administered 
symptom, side-effect, and tolerability questionnaires. Pre-dosing mucus and post-dosing irrigant samples will also 
be atraumatically collected from the nasal cavity for use in exosomal biomarker sampling.  
ARM 2: Phase 2 
The Phase II study will be an open label safety and efficacy expansion cohort using the 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. This sample size was calculated based on a power analysis derived from the 
results of our oral Verapamil trial. The first dose will be administered in in a 10th or 11th floor MEE clinic 
withhemodynamic monitoring. A medically trained member of the study staff with monitor the patient for one 
hour. Patients will be instructed on the how to properly perform the irrigation using a pre-recorded video 
demonstration. If no first-course DLT occurs then patients will continue taking the topical Verapamil dose 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. 
4.2.1 PRIMARY ENDPOINT 
Phase Ib: 
The primary outcome measurement for Phase IB(SA1) will be defining the Maximal Tolerated Dose(MTD) of topical 
Verapamil HCl. Dose Limiting Toxicity will be defined as a development of 2nd or 3rd degree heart block as 
measured by an EKG. 
Phase II:  
The primary outcome for Phase II(SA2) will be determining the efficacy of topical Verapamil HCl at the MTD for 
subjective symptoms of CRSwNP using the validated SNOT-22. 
4.2.2 SECONDARY ENDPOINTS 
Phase Ib: 


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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. 
Mild toxicity will be defined as a Meltzer Compliance Grade of 2-3. 
Phase II: 
The secondary outcomes of Phase II will be to determine the efficacy of Verapamil HCl at the MTD as measured by 
a subjective 10cm visual analog scale(VAS), Meltzer topical irrigation satisfaction and compliance scores, and the 
validated Lund-Kennedy nasal endoscopy score(LKS). 
4.2.3 EXPLORATORY ENDPOINTS 
Phase Ib: 
The efficacy of Verapamil HCl irrigations in the treatment of CRSwNP using validated symptoms outcome test 
(SNOT-22) and a 10cm visual analogue scale (VAS). 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
 
5.1 
PARTICIPANT INCLUSION CRITERIA 
Phase 1 Inclusion: 
 
Patients presenting to the MEEI Sinus Center 
 
Age 18-80 yrs old 
 
Diagnosed with Chronic Rhinosinusitis with Nasal Polyps according to the EPOS 2012 consensus criteria 
Phase 2 Inclusion 
 
Post-operative with a Lund-Kennedy Poly score of <4 
 
Baseline SNOT-22 Score ≥ 30 
 
Patients presenting to the MEEI Sinus Center 
 
Age 18-80 yrs old 
 
Diagnosed with Chronic Rhinosinusitis with Nasal Polyps according to the EPOS 2012 consensus criteria 
5.2 
PARTICIPANT EXCLUSION CRITERIA 
Patients with the following comorbidities: 
•GI Hypomotility 
•Heart Failure 
•Liver Failure 
•Kidney Disease 


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•Muscular Dystrophy 
•Pregnant or Nursing Females 
•Systemic 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 


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•St Johns Wort 
Patients who are unwilling or unable to wash out of systemic steroids 
Patients with cardiac or conduction abnormality picked up by screening EKG 
Post-op patients with surgery within 3 months prior to enrollment. 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION 
A concerted effort will be made to recruit male and female subjects equally. Special attention will also be paid to 
enroll minority subjects into this trial to represent the ethnic demographics of the region as closely as possible. No 
sex/gender or racial/ethnic group will be excluded from this study. 
Patients in the Phase 1B arm will be compensated $150 per visit at the end of their participation to compensate 
them for the frequent nature of the visits. Patients in the Phase 2 arm will be compensated $150 for their  
participation at the end of their week 4 visit.  
All subjects will be recruited from the MEEI Sinus Center. The MEEI Sinus Center has over 3000 outpatient visits per 
year. This should provide a more than adequate patient pool to recruit from. Patients will be informed of the 
Phase 1B or Phase 2 trial during a regular clinical visit. If they express interest in the trial the clinical coordinator 
will explain the parameters of the study and review inclusion/exclusion criteria. 
5.4 
PARTICIPANT WITHDRAWAL OR TERMINATION 
 
5.4.1 REASONS FOR WITHDRAWAL OR TERMINATION 
Arm 1: Phase 1B 
The PI will terminate a Phase IB participant if they experience a DLT, more than one IT, or begin a contradictory 
medication during the course of the trial. Patients may withdraw from the trial at any time upon request. Any 
withdrawn participants from Phase IB will be replaced to maintain 3 patient cohorts. Their reason for withdrawal 
will be noted. 
Arm 2: Phase 2 
The PI will terminate a Phase II study participant if they present with any clinical adverse event (AE) or other 
medical complication such that continued participation in the study would not be in the best interest of the 
participant. The PI will terminate a participant if they miss more than 2 doses of topical Verapamil in a week. 
Compliance will be checked using a patient dosing diary. Participants may withdraw from the trial at any time upon 
request. Any withdrawn participant will be replaced with a new enrollment. 
5.4.2 HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
Patients that withdraw or are terminated from either arm of the study due to an adverse event will be followed for 
up to 1 year to monitor for additional safety data.  


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Phase 1B: Any withdrawn participants will be replaced to maintain 3 patient cohorts.. Their reason for withdrawal 
will be noted. 
Phase 2: Any withdrawn participant will be replaced with a new enrollment. 
5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable cause.  
Written notification, documenting the reason for study suspension or termination, will be provided by the 
suspending or terminating party to the investigator. IIf the study is prematurely terminated or suspended, the PI 
will promptly inform the IRB and will provide the reason(s) for the termination or suspension.  
Circumstances that may warrant termination or suspension include, but are not limited to:  
 
Determination of unexpected, significant, or unacceptable risk to participants including a greater than 
20% AE rate 
 
Demonstration of efficacy that would warrant stopping  
 
Insufficient compliance to protocol requirements  
 
Data that are not sufficiently complete and/or evaluable  
 
Determination of futility  
Study may resume once concerns about safety, protocol compliance, data quality are addressed and satisfy the 
sponsor, IRB and/or FDA. 
6 
STUDY AGENT 
 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION 
 
6.1.1 ACQUISITION 
The Verapamil HCl irrigations will be acquired from the MEEI Pharmacy. Christine Finn, PharmD will be in charge of 
the prepareation of each dose. 
6.1.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Phase Ib 
Verapamil solution for injection, supplied in vials, will be utilized for this phase of the trial. Verapamil solution for 
injection in vials is commercially available through the Pharmacy’s wholesaler (Cardinal Health). Depending on 
specific product availability from the wholesaler, one of the following verapamil solution for injection in vial will be 
used: 
 
Verapamil 10mg/4mL vial (NDC 00409-1144-02, manufacturer = Hospira) **This is the preferred product if 
available in sufficient quantity from the wholesaler.**  
 
Verapamil 5mg/2mL vial (NDC 00409-1144-05, manufacturer = Hospira) 
 
Verapamil 5mg/2mL vial (NDC 51754-0203-02, manufacturer = Exela Pharma Sciences) 
 
Verapamil is not available for use via the nasal irrigation route and must be formulated in Neil Med Sinus Rinse to 
be utilized as an irrigation. 


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Neil Med Sinus Rinse is commercially available through the Pharmacy’s wholesaler (Cardinal Health). The Neil Med 
Sinus Rinse starter kit (with bottle and 5 packets, NDC 05928-0003-08, manufacturer = NeilMed Products, Inc.) and 
Neil Med Sinus Rinse refill packets (NDC 05928-0002-00, manufacturer = Neil Med Products, Inc.) will be used. 
 
Please see attached package inserts (included in appendix) for more information. 
 
6.1.3 PRODUCT STORAGE AND STABILITY 
Verapamil in its commercially available form (vials or syringes) is stored at controlled room temperature (15-30 
degrees C) and protected from light in its original container.  Verapamil commercially available vials and syringes 
are single use products; if any extra medication remains in the original container after preparing the patient-
specific dose it will be discarded. Verapamil will be stored in the Pharmacy in a limited access area and segregated 
from standard pharmacy stock; it will be specifically allocated as a supply for this trial. When patient-specific 
verapamil doses are prepared, the beyond-use dating will be 9 days at refrigerated temperature (2-8 degrees C) 
Neil Med Sinus Rinse in its commercially available form is stored at controlled room temperature (15-30 degrees 
C).  Neil Med packets are for single use only. Neil Med Sinus Rinse will be stored in the Pharmacy in a limited access 
area and segregated from standard pharmacy stock; it will be specifically allocated as a supply for this trial. When 
patient-specific verapamil doses are combined with Neil Med Sinus Rinse, the final product should be used 
immediately.. 
6.1.4 PREPARATION 
Phase Ib 
Patient-specific verapamil doses will be drawn up from the commercially available verapamil vials utilizing aseptic 
technique in an ISO Class 5 biological safety cabinet in the Pharmacy. At the time of use, patients will prepare the 
Neil Med sinus rinse from the packet according to the manufacturer’s directions for preparation.  The patient will 
transfer the verapamil from the Pharmacy-supplied syringe into the bottle containing the Neil Med sinus rinse and 
use immediately for nasal irrigation. 
Phase II 
Patient-specific verapamil doses will be provided in commercially available verapamil syringes. At the time of use, 
patients will prepare the Neil Med sinus rinse from the packet according to the manufacturer’s directions for 
preparation.  The patient will transfer the verapamil from the Pharmacy-supplied syringe into the bottle containing 
the Neil Med sinus rinse and use immediately for nasal irrigation..  
6.1.5 DOSING AND ADMINISTRATION 
Phase Ib: 
Phase Ib participants will receive dosing according to the included escalation schedule. Dosing will go from an 
initial 0.3-3.6mg total residual dose of Verapamil HCl. Phase II Participants will receive the MAD determined by 
Phase Ib. Participants will administer the irrigation BID. A video demonstration on proper administration of the 
irrigation will be shown at the initial study visit. 
6.1.6 ROUTE OF ADMINISTRATION 


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The Verapamil HCl will be administered intranasally.  
6.1.7 STARTING DOSE AND DOSE ESCALATION SCHEDULE 
Phase Ib Verapamil HCl dose will start at a total residual dose of 0.3mg. Dose escalations will be as follows: 0.3mg, 
0.6mg, 1.2mg, 2.4mg, 3.0mg, 3.6mg. Participants will remain on a dose for at least one week before escalating. 
Phase II dose will be determined by Phase Ib. 
6.1.8 DOSE ADJUSTMENTS/MODIFICATIONS/DELAYS 
The Phase Ib dose will only be escalated if a participant has not experienced a DLT or 2 ITs on the previous dose. 
The Phase II dose will not be changed at any point during the 4 week course.  
6.1.9 DURATION OF THERAPY 
Phase Ib participants will undergo therapy for at least 1 week. Total therapy time will be determined by the 
number of dose escalations a participant is given. 
Phase II participants will undergo therapy for 4 weeks. 
6.1.10 TRACKING OF DOSE 
Participants will fill out a dosing calendar which will be checked by study staff at each visit. 
6.1.11 DEVICE SPECIFIC CONSIDERATIONS 
N/a 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES 
Verapamil solution for injection and Neil Med sinus rinse will be ordered and received from the Pharmacy’s 
wholesaler Cardinal Health in an amount sufficient to provide dosing in accordance with the subject enrollment. 
Verapamil and Neil Med sinus rinse will be stored in the pharmacy segregated as stock for this study only 
Separate perpetual inventories will be maintained by the Pharmacy on Drug Accountability Logs for both the 
verapamil and Neil Med sinus rinse (see template log attached).  Transactions including receipt of medication, use 
of medication for compounding dose / dispensation of medication to the subject, and expiration / waste of 
medication will be documented.  In addition, a perpetual line balance indicating the number of containers of 
medication on hand will be documented. 
Verapamil and Neil Med sinus rinse will be dispensed from the Pharmacy for a study subject pursuant to the 
receipt of a study medication prescription form specific to this project. 
7 
STUDY PROCEDURES AND SCHEDULE 
 
7.1 
STUDY PROCEDURES/EVALUATIONS 
7.1.1 STUDY SPECIFIC PROCEDURES  


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Phase 1B: The below procedures are considered non-standard of care and are study specific: 
 
Meltzer Satisfaction and Compliance assessment  
 
Collection of mucus sample from the nasal cavity 
 
Weekly clinical examination  
 
EKG 
Phase 2: The below procedures are considered non-standard of care and are study specific: 
 
Meltzer Satisfaction and Compliance assessment  
 
Collection of mucus sample from the nasal cavity 
 
EKG 
7.1.2 STANDARD OF CARE STUDY PROCEDURES  
Phase 1B: The below procedures are considered routine standard of care in the management of patients with 
CRSwNP: 
 
Nasal Endoscopy with scoring 
 
SNOT-22 and VAS assessment for disease severity 
Phase 2: The below procedures are considered routine standard of care in the management of patients with 
CRSwNP: 
 
Nasal Endoscopy with scoring 
 
SNOT-22 and VAS assessment for disease severity 
 
Clinic examination every 2-4 weeks in patients with CRSwNP 
7.2 
LABORATORY PROCEDURES/EVALUATIONS 
 
7.2.1 CLINICAL LABORATORY EVALUATIONS  
Screening: A pregnancy test will be done within 24 prior to the first application of topical verapamil in women of 
child bearing age. 
7.2.2 OTHER ASSAYS OR PROCEDURES 
Exosome Purification: Mucus samples will be extracted from the PVA sponge by centrifugation (1500g at 4˚C for 30 
minutes). The mucus and irrigant samples will then be diluted in 150 µL of 1x phosphate buffered saline (PBS, Life 
Technologies, Carlsbad, CA) with Protease Inhibitor Cocktail (1:100, Sigma, St. Louis, MO). A portion of the whole 
mucus sample will be saved for cytokine analysis. Exosomes will then be isolated by ultracentrifugation(UCF) as 
described by Théry et al[63]. Cellular debris will be pelleted by centrifugation at 45 min at 12,000 × g at 4°C. The 
supernatant will then be suspended in 4.5mL of PBS in polypropylene tubes (Thinwall, 5.0 mL, 13 x 51 mm, 
Beckman Coulter, Indianapolis, IN) and ultracentrifuged for 2 hours at 110,000 × g, at 4°C. The supernatant will 
then be collected and the pellet will be resuspended in 4.5 mL 1x PBS. The suspension will be filtered through a 


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0.22-μm filter (Fisher Scientific, Pittsburgh, PA) and collected in a fresh ultracentrifuge tube. The filtered 
suspension will then be centrifuged for 70 min at 110,000 × g at 4°C. The supernatant will then be collected and 
the pellet will be resuspended in 200 μl PBS with protease inhibitor. The exosome concentration of each pellet will 
be determined using a commercially available enzyme linked immunosorbent assay(ELISA) for the established 
exosome markers CD63 and CD9(ExoELISA, System Biosciences, Palo Alto, CA) as previously described[64]. 
Transmission Electron Microscopy(TEM): The presence of intact exosomes after UCF will be verified by TEM as 
previously described(Figure 3.5). Isolated exosomes will be fixed for 1 hour at room temperature in 2% 
paraformaldehyde in 0.1M sodium phosphate buffer (Electron Microscopy Sciences, Hatfield, PA). 5 µL of the 
exosomes will be absorbed on to Formvar-carbon coated electron microscopy grids (Electron Microscopy Sciences) 
for 20 minutes. After absorption, the grids will be rinsed in PBS 3 times and then transferred to PBS/50 mM glycine 
(Sigma Aldrich, St. Louis MO) for 4 washes. The grids will then be blocked in 5% Bovine Serum Albumin (BSA, Fisher 
Scientific) in 1x phosphate buffered saline (buffer) for 10 minutes at room temperature. The grids will then be 
incubated at 4ºC overnight in the primary antibody (1:25, Purified Mouse Anti-Human CD63 Clone H5C6, BD 
Biosciences) diluted in 1% BSA buffer.  The grids will then be rinsed in 0.1% BSA buffer and then 0.5% BSA buffer 6 
times each. Then the secondary Protein-G antibody (1:20 in 1%BSA buffer, EM Grade, 10nm, Electron Microscopy 
Services, Hatfield, PA) in 5% BSA buffer will be applied for 1 hour at room temperature and rinsed 8 times with 1x 
PBS. The grids will be incubated in 1% glutaraldehyde in 0.1M sodium phosphate buffer (Electron Microscopy 
Services) for 5 minutes.  After rinsing 8 times in deionized water, the grids will be contrasted in uranyl-oxalate 
solution, pH 7 (UA, Electron Microscopy Services) for 5 minutes. The grids will be blotted on filter paper and air 
dried prior to imaging. The exosomes will be observed using a FEI Tecnai G2 Spirit transmission electron 
microscope (FEI, Hillsboro, Oregon) at an accelerating voltage of 100 kV interfaced with an AMT XR41 digital CCD 
camera (Advanced Microscopy Techniques, Woburn, Massachusetts) for digital TIFF file image acquisition. Rabbit 
IgG (Vector Laboratories, Burlingame, CA) and CD63 lysate (Novus Biologicals CD63 Overexpression Lysate (Native), 
Fisher Scientific) will be used as negative and positive controls, respectively.  
Exosomal P-gp, Whole Mucus, and Irrigant Th2 Cytokine Quantification: Whole mucus and exosomal P-gp will be 
quantified using a commercially available ELISA(USCN Life Sciences Inc., Wuhan, P.R. China) kit as previously 
described. Western blot will be used to confirm the ELISA findings. Briefly, 10 μg of total protein and Laemmli 
loading buffer (2x Laemmli sample buffer, Bio-Rad, Hercules, CA, with β-mercaptoethanol, Sigma, St. Louis, MO) 
will be denatured at 95˚C for 3 minutes and separated on precast Novex® 4-20% Tris-Glycine Mini Protein Gels (1.0 
mm, 9 wells, Life Technologies). Protein will be transferred onto a polyvinylidene fluoride membrane by iBlot® Dry 
Blotting System (Invitrogen, Carlsbad, CA). The membrane will be blocked and the primary antibody (Monoclonal 
Anti-P-glycoprotein Clone F4, 1:1000, in 5% milk in TBST) will be added and incubated at 4˚C overnight. After 3 
washes of 15 minutes each with TBST, the secondary antibody (Anti-Mouse IgG (Fab specific)–Peroxidase antibody 
produced in goat in 5% milk in TBST, Sigma) will be incubated for 1 hour at room temperature. The membrane will 
be washed again 3 times at 15 minutes each with TBST and SuperSignal™ West Pico Chemiluminescent Substrate 
(Life Technologies) will be applied for 5 minutes before visualization with ChemiDoc MP(Bio-Rad). Recombinant P-
gp (USCN Life Sciences Inc., Wuhan, P.R. China) will be used as a control and a monoclonal anti-GAPDH antibody 
produced in mouse (Sigma Aldrich) will be used as a loading control. Pre and post-treatment Th2 associated 
cytokines in whole mucus and irrigant efflux including Eotaxin-3, Eosinophilic Cationic Protein(ECP), IL-6, IL-5, and 
TSLP which have been previously associated with successful CRSwNP treatment response[36][30][3][45] will be 
tested by commercially available ELISA. 
7.2.3 SPECIMEN PREPARATION, HANDLING, AND STORAGE 


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Mucus will be taken from the middle meatus by placing a compressed polyvinyl alcohol sponge (PVA, Medtronic, 
Minneapolis, MN) within the internal valve for 5 minutes taking care not to abrade the mucosa or contaminate the 
sponge with blood. The irrigant efflux will be collected in sterile 50mL conical tubes. All samples will be stored in -
80°C freezers in the Eaton-Peabody Laboratories(EPL) at MEEI.  
7.2.4 SPECIMEN SHIPMENT 
N/a 
7.3 
STUDY SCHEDULE 
 
7.3.1 SCREENING 
Phase 1B: 
During the screening visit all exclusion/unclusion criteria will be reviewed. If a participant is a good candidate for 
the study consent will be obtained. Participants will be given an intake questionnaire which queires the presence 
of a variety of medical parameters which are relevant to the disease process. A pregnancy test will be administered 
to any female of child bearing age who is sexually active and not using contraception or admits to a possbility of 
being pregnant. If the participant has used systemic steroids within the past 3 weeks they will be asked to undergo 
a 3 week washout of steroids before beginning the trial. 
Phase 2: 
During the screening visit all exclusion/inclusion criteria will be reviewed. If a participant is a good candidate for 
the study consent will be obtained. Participants will be given an intake questionnaire which queires the presence 
of a variety of medical parameters which are relevant to the disease process. A pregnancy test will be administered 
to any female of child bearing age who is sexually active and not using contraception or admits to a pissbility of 
being pregnant. If the participant has used systemic steroids within the past 3 weeks they will be asked to undergo 
a 3 week washout of steroids before beginning the trial. 
7.3.2 ENROLLMENT/BASELINE 
Phase 1B: 
Participants will fill out the baseline questionnaires (SNOT-22, VAS). An endoscopy will be recorded and scored. A 
mucus sample will be collected from the nasal cavity with a small sponge.Participants will be instructed in the 
proper method for using the verapamil irrigation. They will then be given a baseline EKG and asked to perform the 
first verapamil irrigation while being monitored for 1 hour by clinical monitoring equipment and study staff. After 
monitoring the patients will be given a second EKG. The irrigant will be collected. If no EKG abnormalities that are 
deemed unsafe by the study safety officer are detected during or after the initial irrigation the participants will be 
prescribed the rest of the verapamil rinse. 
Phase 2: 
Participants will fill out the baseline questionnaires (SNOT-22, VAS). An endoscopy will be recorded and scored. A 
mucus sample will be collected from the nasal cavity with a small sponge. Participants will be instructed in the 
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first verapamil irrigation while being monitored for 1 hour by clinical monitoring equipment and study staff. After 
monitoring the patients will be given a second EKG. The irrigant will be collected.. If no EKG abnormalities that are 
deemed unsafe by the study safety officer are detected during or after the initial irrigation the participants will be 
prescribed the rest of the verapamil rinse. 
7.3.3 FOLLOW-UP  
Phase 1B: 
Participants will asked to fill out a SNOT-22, VAS, , Satisfaction scale, and Compliance scale. Adherence to the 
treatment regimen will be evaluated. An endoscopy will be recorded and scored. A mucus sample will be collected 
from the nasal cavity with a small sponge. Participants will be evaluated for side-effects. An EKG will be taken. If no 
intermediate toxicity or DLT is experienced the participant will be moved up to the next dose. Participants will be 
asked to perform the initial irrigation of their next dose while being monitored for 1 hour by clinical monitoring 
equipment. After monitoring the patients will be given a second EKG. The irrigant will be collected. If no EKG 
abnormalities that are deemed unsafe by the study safety officer are detected during or after the initial irrigation 
the participants will be prescribed the rest of the verapamil rinse. 
Phase 2: 
During the Week 1 follow-up visit participants will asked to fill out a SNOT-22, VAS, , Satifscation scale, and 
Compliance scale. Adherence to the treatment regimen will be evaluated. Participants will be evaluated for side-
effects. An EKG will be taken. An endoscopy will be recorded and scored. 
7.3.4 FINAL STUDY VISIT 
Phase 1B: 
Participants will have their final study visit when they experience DLT and are removed from the study, choose to 
end their participation, or achive the maximal administered dose. The reason for the drop-out will be noted in the 
participant file. Participants will be asked to fil out a SNOT-22, VAS, Satisfaction scale, and Compliance scale and 
will be evaluated for side-effects.  An endoscopy will be recorded and scored. A mucus sample will be collected 
from the nasal cavity with a small sponge. Participants will receive their compensation at the end of the final visit.  
Phase 2: 
During the Week 4 visit participants will be asked to fill out a SNOT-22, VAS, Satisfaction scale, and Compliance 
scale. Adherence to the treatment regimen will be evaluated. Participants will be evaluated for side-effects. An 
endoscopy will be recorded and scored. A mucus sample will be collected from the nasal cavity with a small 
sponge. Participants will receive their compensation at the end of the final visit. 
7.3.5 EARLY TERMINATION VISIT 
In the event of an early termination participants will be asked to perform all the procedures for the final visit 
(Phase 1B and 2) at their final visit. 
 


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7.3.7 SCHEDULE OF EVENTS TABLE 
 
 
7.4 
JUSTIFICATION FOR SENSITIVE PROCEDURES 
N/a 
7.5 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES  
7.5.1 PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES 
 
Participants will be asked to abstain from consuming grapefruit, limes, or pomelos while using the study 
medication.  
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES  
The following drugs will not be permitted for concomitant use with Verapamil HCl: AspirinBeta-blockers, 
Cimetidine(Tagamet), Clarithromycin(Biaxin), Cyclosporin, Digoxin, Disopyramide(Norpace), Diuretics, 
Erythromycin, Flecainide, HIV Protease Inhibitors(Indinavir, Nelfinavir, Ritonavir), Quinidine, Lithium, Pioglitazone, 
Rifampin, and St Johns Wort. 
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES  
N/a 
7.8 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES  


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N/a 
7.9 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE  
Participants will not have access to intranasal Verapamil HCl after the trial. 
8 
ASSESSMENT OF SAFETY 
 
8.1 
SPECIFICATION OF SAFETY PARAMETERS 
Safety parameters that are also endpoints for Phase Ib are: 
 
a development of 2nd or 3rd degree heart block as measured by an EKG. 
 
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  
All safety parameters will be recorded in a partcipants CRF at each study visit. All AEs will require reporting for the 
protection of human subjects. 
If a heart block develops, treatment will be adjusted based on symptomatology. Completely asymptomatic 
patients can be observed. Patients with mild to moderate symptoms (hypotension, orthostasis, fatigue, dyspnea or 
angina) should be treated with 1liter NS bolus followed by Calcium Gluconate.  Patients who are severely 
symptomatic and have failed the above interventions can also receive glucagon, norepinephrine, and finally pacing 
if necessary 
8.1.1 DEFINITION OF ADVERSE EVENTS (AE) 
An adverse event will be defined as any untoward medical occurrence associated with the use of intranasal 
Verapamil HCl, whether or not it is considered related to the intervention.  
8.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
An AE or suspected adverse reaction is considered "serious" if, in the view of either the investigator or sponsor, it 
results in any of the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions, or a congenital anomaly/birth defect. Important medical events that may not 
result in death, be life-threatening, or require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.  
8.1.3 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
OHRP considers unanticipated problems involving risks to participants or others to include, in general, any 
incident, experience, or outcome that meets all of the following criteria:  


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• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and informed consent 
document; and (b) the characteristics of the participant population being studied;  
• 
Related or possibly related to participation in the research (“possibly related” means there is a reasonable 
possibility that the incident, experience, or outcome may have been caused by the procedures involved in the 
research); and  
• 
Suggests that the research places participants or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized.  
 
This study will use the OHRP definition of UP 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT 
 
8.2.1 SEVERITY OF EVENT 
 
For AEs not included in the protocol defined grading system, the following guidelines will be used to describe 
severity.  
 
 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily activities.  
 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning.  
 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug therapy or 
other treatment. Severe events are usually potentially life-threatening or incapacitating. 
 
8.2.2 RELATIONSHIP TO STUDY AGENT 
 
The clinician’s assessment of an AE's relationship to study agent (drug, biologic, device) is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the study. If there is any 
doubt as to whether a clinical observation is an AE, the event should be reported. All AEs must have their 
relationship to study agent assessed. In a clinical trial, the study product must always be suspect. To help assess, 
the following guidelines are used.  
 
Related – The AE is known to occur with the study agent, there is a reasonable possibility that the study 
agent caused the AE, or there is a temporal relationship between the study agent and event. Reasonable 
possibility means that there is evidence to suggest a causal relationship between the study agent and the 
AE.  
 
Not Related – There is not a reasonable possibility that the administration of the study agent caused the 
event, there is no temporal relationship between the study agent and event onset, or an alternate 
etiology has been established  
8.2.3 EXPECTEDNESS  
Dr. Bleier will be responsible for determining whether an AE is expected or unexpected. An AE will be considered 
unexpected if the nature, severity, or frequency of the event is not consistent with the risk information previously 
described for the study agent. 


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8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
Participants will be assessed for AEs during each study visit. All AEs including local and systemic reactions not 
meeting the criteria for SAEs will be recorded in the CRF. Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study product (assessed only by 
those with the training and authority to make a diagnosis), and time of resolution/stabilization of the event. All 
AEs will be followed to adequate resolution.  
 
Any medical condition that is present at the time that the participant is screened will be considered as baseline 
and not reported as an AE. However, if the study participant’s condition deteriorates at any time during the 
study, it will be recorded as an AE. UPs will be recorded in the participant file throughout the study.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event at each 
level of severity to be performed. AEs characterized as intermittent require documentation of onset and duration 
of each episode.  
The PI will record all reportable events with start dates occurring any time after informed consent is obtained until 
7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study participation. At each study visit, the 
investigator will inquire about the occurrence of AE/SAEs since the last visit. Events will be followed for outcome 
information until resolution or stabilization 
8.4 
REPORTING PROCEDURES 
 
8.4.1 ADVERSE EVENT REPORTING  
All AE’s will be reported to both the IRB and DSMB. SAEs will be reported within 24 hours of investigator 
awareness and non-serious AEs will be reported within 7 days of investigator awareness. The study coordinator 
will compile a formal report of the event and corrective steps for both the DSMB and IRB. The investigator will be 
responsible for signing off on AE reports and submitting them to the DSMB and IRB. 
8.4.2 SERIOUS ADVERSE EVENT REPORTING  
 
The study clinician will complete a SAE Form within the following timelines:  
 
All deaths and immediately life-threatening events, whether related or unrelated, will be recorded on the 
SAE Form and submitted to the DCC/study sponsor within 24 hours of site awareness. See Section 1, Key 
Roles for contact information. 
 
Other SAEs regardless of relationship, will be submitted to the DCC/study sponsor within 72 hours of site 
awareness.  
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to be chronic or 
the adherence to be stable. Other supporting documentation of the event may be requested by the DCC/study 
sponsor and should be provided as soon as possible. The study sponsor will be responsible for notifying FDA of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible but in no case later than 7 
calendar days after the sponsor's initial receipt of the information. 


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8.4.3 UNANTICIPATED PROBLEM REPORTING  
 
Incidents or events that meet the OHRP criteria for UPs require the creation and completion of an UP report 
form. It is the site investigator’s responsibility to report UPs to their IRB. The UP report will include the 
following information:  
 
Protocol identifying information: protocol title and number, PI’s name, and the IRB projectnumber; 
 
A detailed description of the event, incident, experience, or outcome; 
 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP 
 
A description of any changes to the protocol or other corrective actions that have been taken or are 
proposed in response to the UP. 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:  
 
UPs that are SAEs will be reported to the IRB within 24 hours of the investigator becoming aware of the 
event. 
 
Any other UP will be reported to the IRB within 7 days of the investigator becoming aware of the problem. 
8.4.4 EVENTS OF SPECIAL INTEREST  
N/a 
8.4.5 REPORTING OF PREGNANCY  
Pregnant women will be excluded from this trial. If a participant becomes pregnant during the trial they will be 
withdrawn and treatment will be immediately halted. The participant will then have safety follow-ups during the 
course of their pregnancy.  
8.5 
STUDY HALTING RULES  
Administration of study agent will be halted if the trial reaches a 20% AE rate and enrollment screens will stop 
accepting new study participants. The PI will inform the DSMB members within 24 hours of this occurrence and 
will provide the DSMB with AE listing reports. The DSMB will convene an ad hoc meeting by teleconference or in 
writing as soon as possible. The DSMB will provide recommendations for proceeding with the study to the PI. The 
PI will inform the FDA of the temporary halt and the disposition of the study. 
8.6 
SAFETY OVERSIGHT 
Safety oversight will be under the direction of a DSMB composed of individuals with the appropriate expertise, 
including Dr. Jeremy Goldfarb, Dr. Christine Finn, and Dr. Hang Lee. The DSMB will meet at least semiannually to 
assess safety and efficacy data on each arm of the study. The DMSB will operate under the rules of an approved 
charter that will be written and reviewed at the organizational meeting of the DSMB. At this time, each data 
element that the DSMB needs to assess will be clearly defined. The DSMB will provide its input to the PI and study 
staff. 
9 
CLINICAL MONITORING 


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Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects are protected, that 
the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial is in compliance 
with the currently approved protocol/amendment(s), with Good Clinical Practice(GCP), and with applicable 
regulatory requirements(s). A Data Safety Monitoring Board(DSMB, see section 11) will be established to monitor 
the study. The DSMB will meet at least twice a year. During Phase Ib the DSMB will monitor the study after the first 
3 participants are enrolled and then every 6 patients after that. During Phase II the DSMB will monitor the study 
after 50% (10 participants) of enrollment has been reached. The DSMB will review all efficacy and safety data and 
give the PI a report of their findings. The PI will perform internal quality management of study conduct, data 
collection, documentation, and completion. All EKG and hemodynamic data will be reviewed by a medical 
internist/ anesthesiologist(JG) who also will act as the chair the DSMB.  
The PI will perform internal quality management of study conduct, data collection, documentation and 
completion.  
10 
STATISTICAL CONSIDERATIONS  
 
10.1 
STATISTICAL AND ANALYTICAL PLANS 
All statistical analyses will be performed in conjunction with the consultant biostatistician(Dr. Hang Lee). The 
proposed sample size of 20 subjects for the Phase II expansion cohort was determined to detect, with an 80% 
power at a 5% type-1 error rate, a change of 15.9 points on the primary endpoint (ie. SNOT-22 score) between 
baseline and 4 weeks. This calculation was based on two assumptions. The first is a target effect size of 15.9 which 
represents a conservative value derived from the established MCID for the SNOT-22 of 8.9[65] and the LSM change 
in SNOT-22 of 27.7 derived from our previous trial of oral Verapamil(Section R.4.d)[19]. The second is an 
anticipated standard deviation of 24 which is calculated from the standard deviations of 30 both at the baseline 
and 8 week time point observed in our oral Verapamil trial and an r2 of 50% between the two time points.  With a 
significance level of 0.05, a standard deviation of 24, and 80% power, a sample size of 20 would be needed to 
detect a difference of 15.9. Analysis of efficacy will be based on an intention-to-treat population that will include 
all enrolled patients. A mixed-effect model with repeated measures approach will be used to independently 
analyze the change in the SNOT-22, VAS, and LKS. An intraclass correlation coefficient (ICC) will be calculated to 
assess inter-rater agreement with respect to the LKS scores. Descriptive statistics will be used for demographics, 
baseline characteristics, and safety variables. Linear regression models will be fitted to examine the interaction 
effect between baseline characteristics, whole mucus and exosomal P-gp concentrations, mucus and irrigant 
cytokine concentrations, and treatment on change in SNOT-22 while adjusting for the baseline SNOT-22 score. 
Statistical analyses will be performed using the statistical software SAS (SAS Institute Inc., Cary, NC) 
10.2 
STATISTICAL HYPOTHESES 
 
Primary Efficacy Endpoints: SNOT-22 
o 
H0: There is no means difference between baseline SNOT-22 scores and 4 week SNOT-22 scores 
 
Secondary Efficacy Endpoints: VAS and LKS 
o 
H0: There is no means difference between baseline VAS scores and 4 week VAS scores 
o 
H0: There is no means difference between baseline LKS scores and 4 week LKS scores 
10.3 
ANALYSIS DATASETS 


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Phase Ib: 
All patients in the Phase Ib arm will be part of the Safety Analysis Dataset 
Phase II: 
The Phase II participants will be included in an intention-to-treat dataset and a safety analysis dataset.  
Participants who used at least 80% of the topical verapamil during the one month period will be considered an 
evaluable dataset. 
10.4 
DESCRIPTION OF STATISTICAL METHODS 
 
10.4.1 GENERAL APPROACH 
Phase Ib: 
Phase Ib will be an intra-pateint, accelerated titration design. The analysis of the safety endpoints will be 
presented with means and standard deviations of their occurance within the study population. 
Phase II: 
Phase II will be an open-label trial. Efficacy and safety outcomes will be presented with means and standard 
deviations. 
10.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
Data for the primary efficacy endpoints will be tested to determine if they are parametric. For parametric data the 
differences between the baseline and subsequent visits will be tested using a Student’s t-test. Non-parametric data 
may be tested using the Mann Whitney U test. Additional statistical methods may be utilized if required. Any 
deivations from the previously approved statistical plan will be described and justified in a protocol amendment 
and/or in the final report submitted to this application.  
10.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Data for the secondary endpoints will be analyzed using the same methods as the primary endpoints. 
10.4.4 SAFETY ANALYSES 
The safety of the drug will be determined by analyzing the rate of adverse events in both phases of the trial. An 
occurance of 10% within the study population will be considered significant.  
10.4.5 ADHERENCE AND RETENTION ANALYSES 
Adherence to the dosing schedule will be tracked with a dosing calendar that participants will fill out daily. This 
calendar will be assessed by the study staff at each visit.  
10.4.6  BASELINE DESCRIPTIVE STATISTICS 


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Baseline statistics will be calculated using means (standard deviations) and numbers (percentages).  
10.4.7 PLANNED INTERIM ANALYSES  
 
10.4.7.1 
SAFETY REVIEW 
Phase Ib: 
This arm will be halted when the MTD has been determined. The proposed safety endpoints will be monitored at 
each weekly visit. Participants will be formally queried for medication related side effects and will undergo an EKG 
at each visit, which will be assessed by a medical internist/anesthesiologist.  
Phase II: 
This arm will be halted if 20% of the population experiences a severe adverse event. This decision will be made at 
the discretion of the DSMB. Safety endpoints will be monitored at each of the 3 study visits (baseline, week 1, 
week 4). Participants will be formally queried for medication related side effects and will undergo a repeat EKG at 
the week 1 visit, which will be assessed by a medical internist/anesthesiologist. 
10.4.7.2 
EFFICACY REVIEW 
No interim analysis will be performed in either arm of this trial. 
10.4.8 ADDITIONAL SUB-GROUP ANALYSES 
Phase Ib: 
The primary safety endpoints will not be sub-divided by demographic characteristics.  
Phase II: 
The primary endpoint, SNOT22 score, analysis will not be sub-divided by demographic characteristics. 
10.4.9 MULTIPLE COMPARISON/MULTIPLICITY 
N/a 
10.4.10 
TABULATION OF INDIVIDUAL RESPONSE DATA 
Individual participant data will be listed be listed by visit number. In Phase Ib visits will be numbered (1,2,3…) by 
how many visits the participant has before they reach the MTD. In Phase 2 visits will be listed (baseline, week 1, 
week 4) per the schedule of events. 
10.4.11 
EXPLORATORY ANALYSES 
N/a 
10.5 
SAMPLE SIZE 


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The sample size for the Phase II arm was determined in consultation with Dr. Hang Lee (biostatistician). It is based 
on the MCID for the SNOT-22 and the least suare means value for the SNOT-22 that was determined by the 
previous oral verapamil trial conducted by Dr. Bleier. The new, combined MCID for the SNOT-22 was determined 
to be 15.9. The standard deviation for this trial is 24. This was calculated using the standard deviation of the oral 
verapamil trial (30) and an r2 of 50%.  With a significance level of 0.05, a standard deviation of 24, and 80% power, 
a sample size of 20 is needed to detect a difference of 15.9. 
10.6 
MEASURES TO MINIMIZE BIAS 
 
10.6.1 ENROLLMENT/ RANDOMIZATION/ MASKING PROCEDURES 
Participants will be enrolled in the MEEI Sinus Center. Eligible patients will be informed about the trial by their 
physician in the Sinus Center. If they express interest a member of the study staff will enroll them after passing 
through all inclusion and exclusion criteria. There will be no blinding or randomization in either phase of this trial.  
10.6.2 EVALUATION OF SUCCESS OF BLINDING  
N/a 
10.6.3 BREAKING THE STUDY BLIND/PARTICIPANT CODE 
N/a 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
A Case Report Form (CRF) will be completed for each subject enrolled into the clinical study. The PI and/or their 
designee will review, approve and sign/date each completed CRF; the PI and/or designee’s signature serving as 
attestation of the PI’s responsibility for ensuring that all clinical and laboratory data entered on the CRF are 
complete, accurate and authentic. Source Data are the clinical findings and observations, test data, and other 
information contained in Source Documents.  Source Documents are the original records (and certified copies of 
original records); including, but not limited to, hospital medical records, physician or office charts, physician or 
nursing notes, subject diaries or evaluation checklists, pharmacy dispensing records, and recorded data from 
automated instruments.  When applicable, information recorded on the CRF shall match the Source Data recorded 
on the Source Documents. The EKG findings, SNOT-22, VAS, Side Effects, LKS, satisfaction, and compliance data will 
be recorded on the CRF which will serve as the primary source data for these data elements. Each form will be 
recorded in a study chart which is linked to the subject’s study ID number. An electronic image capture system will 
be used to record nasal endoscopy which will be maintained on an encrypted MEEI server. 
12 
QUALITY ASSURANCE AND QUALITY CONTROL 
The PI and DSMB will verify that the study is conducted and data are generated, documented, and reported in 
compliance with the protocol, GCP, and the applicable regulatory requirements (e.g. FDA, Clinicaltrials.gov). The PI 
and study staff will provide direct access to all source data/documents and reports for the purpose of monitoring 
and auditing by the DSMB, and inspection by local and regulatory authorities.  
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS  


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13.1 
ETHICAL STANDARD  
The PI will ensure that this study is conducted in full conformity with Regulations for the Protection of Human 
Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, and/or the ICH E6. 
13.2 
INSTITUTIONAL REVIEW BOARD  
The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted to 
the IRB for review and approval. Approval of both the protocol and the consent form must be obtained before any 
participant is enrolled. Any amendment to the protocol will require review and approval by the IRB before the 
changes are implemented to the study. All changes to the consent form will be IRB approved; a determination will 
be made regarding whether previously consented participatns need to be re-consented.  
13.3 
INFORMED CONSENT PROCESS  
 
13.3.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Consent forms describing in detail the study agent, study procedures, and risks are given to the participants and 
written documentation of informed consent is required prior to starting administering the study drug. The 
following materials are submitted with this protocol: 
 
Informed consent form 
 
Informed consent script 
13.3.2 CONSENT PROCEDURES AND DOCUMENTATION 
Extensive discussion of risks and possible benefits of participation will be provided to the participants and their 
families. Consent forms will be IRB-approved and the participant will be asked to read and review the 
document. The PI and/or designee will explain the research study to the participant and answer any questions 
that may arise. All participants will receive a verbal explanation in terms suited to their comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research participants. Participants 
will have the opportunity to carefully review the written consent form and ask questions prior to signing. The 
participants will have the opportunity to discuss the study with their surrogates or think about it prior to 
agreeing to participate. The participant will sign the informed consent document prior to any procedures being 
done specifically for the study. The participants may withdraw consent at any time throughout the course of 
the trial. A copy of the informed consent document will be given to the participants for their records. The rights 
and welfare of the participants will be protected by emphasizing to them that the quality of their medical care 
will not be adversely affected if they decline to participate in this study. 
 
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY  
 
Participant confidentiality is strictly held in trust by the participating investigators and their staff. This 
confidentiality is extended to cover testing of biological samples in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information generated will be held 


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in strict confidence. Participants will be linked to their information with a coded identification number. No 
information concerning the study or the data will be released to any unauthorized third party without prior 
written approval of the PI.  
 
The DSMB, representatives of the IRB or any other regulatory agency may inspect all documents and records 
required to be maintained by the investigator, including but not limited to, medical records (office, clinic, or 
hospital) and pharmacy records for the participants in this study. The clinical study site will permit access to such 
records.  
The study participant’s contact information will be securely stored at the clinical site for internal use during the 
study. At the end of the study, all records will continue to be kept in a secure location for as long a period as 
dictated by local IRB and Institutional regulations.   
13.4.1 RESEARCH USE OF STORED HUMAN SAMPLES,SPECIMENS OR DATA 
Samples and data collected under this protocol may be used to study CRSwNP. No genetic testing will be 
performed. 
Access to stored samples to be limited using a locked freezer at MEEI. Samples and data will be stored using codes 
assigned by the PI. Data will be kept in password-protected computers. Only the PI and study staff will have access 
to the samples and data. Study participants who request destruction of samples will be notified of compliance with 
such request and all supporting details will be maintained.   
13.5 
FUTURE USE OF STORED SPECIMENS  
Data collected for this study will be analyzed and stored at MEEI. Samples stored for this study will not be used for 
future research projects.  
 
14 
DATA HANDLING AND RECORD KEEPING  
 
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection is the responsibility of the clinical trial staff under the supervision of the PI. The investigator is 
responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data reported.  
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of data. 
Black ink is required to ensure clarity of reproduced copies. When making changes or corrections, cross out the 
original entry with a single line, and initial and date the change. DO NOT ERASE, OVERWRITE, OR USE CORRECTION 
FLUID OR TAPE ON THE ORIGINAL.  
 
14.2 
STUDY RECORDS RETENTION  
Study documents should be retained for a minimum of 2 years after the last approval of marketing application in 
an ICH region and until there are no pending or contemplated marketing applications in an ICH region or until at 
least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. 


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These documents should be retained for a longer period, however, if required by local regulations. It is the 
responsibility of the PI to inform the study staff when these documents no longer need to be retained.  
14.3 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol or GCP requirements. The noncompliance 
may be either on the part of the participant, the investigator, or the study staff. As a result of deviations, corrective 
actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH E6:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 
It is the responsibility of the site to use continuous vigilance to identify and report deviations within 7 working days 
of identification of the protocol deviation, or within 7 working days of the scheduled protocol-required activity. All 
deviations must be addressed in study source documents. Protocol deviations must be sent to the local IRB per 
their guidelines. The site PI/study staff is responsible for knowing and adhering to their IRB requirements.  
14.4 
PUBLICATION AND DATA SHARING POLICY 
 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted a clinical trials 
registration policy as a condition for publication. The ICMJE defines a clinical trial as any research project that 
prospectively assigns human subjects to intervention or concurrent comparison or control groups to study the 
cause-and-effect relationship between a medical intervention and a health outcome. Medical interventions include 
drugs, surgical procedures, devices, behavioral treatments, process-of-care changes, and the like. Health outcomes 
include any biomedical or health-related measures obtained in patients or participants, including pharmacokinetic 
measures and adverse events. The ICMJE policy, and the Section 801 of the Food and Drug Administration 
Amendments Act of 2007, requires that all clinical trials be registered in a public trials registry such as 
Clinicaltrials.gov, which is sponsored by the National Library of Medicine. Other biomedical journals are 
considering adopting similar policies. For interventional clinical trials performed under NIH IC grants and 
cooperative agreements, it is the grantee’s responsibility to register the trial in an acceptable registry, so the 
research results may be considered for publication in ICMJE member journals. The ICMJE does not review specific 
studies to determine whether registration is necessary; instead, the committee  
recommends that researchers who have questions about the need to register err on the side of registration or 
consult the editorial office of the journal in which they wish to publish.  
FDAAA mandates that a "responsible party" (i.e., the sponsor or designated principal investigator) register 
and report results of certain "applicable clinical trials":  
• 
Trials of Drugs and Biologics: Controlled, clinical investigations, other than Phase I investigations,of a 
product subject to FDA regulation; 
• 
Trials of Devices: Controlled trials with health outcomes of a product subject to FDA regulation(other than 
small feasibility studies) and pediatric postmarket surveillance studies. 


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15 
STUDY ADMINISTRATION 
 
15.1 
STUDY LEADERSHIP 
N/a 
 
16 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is 
critical. Therefore any actual conflict of interest of persons who have a role in the degisn, conduct, analysis, 
publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived 
conflict of interest will be required to have such conflicts amanged in a way that is appropriateto their 
participation in the tiral. The study leadership has established policies and procedures for all study group members 
to disclose oall conclits of interest and will establish a mechanism for the management of all reported dualities of 
interest. 
17  
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APPENDIX 
 
Version 
Date 
Significant Revisions