Clinical trial NCT03119181
Conditions: Healthy Volunteer
Sponsor: Tusker Medical
Start date: 2017-04-27; Completion date: 2017-05-11
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A prospective, multicenter study to determine if active Tymbion iontophoresis is superior to sham Tymbion iontophoresis in providing anesthesia to the tympanic membrane (TM). The study will use the Tula iontophoresis systems for healthy adult volunteers in an office setting, called Group A of Protocol CPR007003.

The protocol CPR007003 also includes a Group B study described in a separate Registration (NCT03197558).

Detailed description:
The objective of the study is to determine if active Tymbion iontophoresis is superior to sham Tymbion iontophoresis in providing anesthesia to the tympanic membrane. In addition, safety will be evaluated by review of the occurrence of adverse events.

The iontophoresis system (IPS) will be used to facilitate anesthetic delivery to the tympanic membrane (TM). The lidocaine-based solution used for local anesthesia of the TM is Tymbion (2% lidocaine HCl/ 1:100,000 epinephrine).

Group A will consist of 40 evaluable healthy adult subjects randomized (1:1) to receive unilateral treatment (1 ear) with either active Tymbion iontophoresis or sham Tymbion iontophoresis. The sham iontophoresis procedure will be identical to the active Tymbion iontophoresis, with the exception that the iontophoresis current will not be activated (ie, the same drug solution will be applied to ears in both arms). After the completion of the iontophoresis procedure, the tympanic membrane will be tapped with a dull otologic probe to test the level of anesthesia. The subject will rate the level of pain using the Visual Analogue Scale (VAS) immediately after the tap. Investigators and subjects will be blinded to treatment assignment.

Safety assessments will be done post procedure and at follow as applicable.

Arms: arm 1: Unilateral treatment with active iontophoresis of Tymbion (2% lidocaine HCl/ 1:100,000 epinephrine) using the Tusker Medical Tula Iontophoresis System. arm 2: The sham iontophoresis procedure will be identical to the active Tymbion iontophoresis in that Tymbion (2% lidocaine/ 1:100,000 epinephrine solution) will be placed in the external ear canal, however the iontophoresis current delivery (which facilitates penetration of drug into the tympanic membrane tissue) will not be activated.
Interventions: intervention 1: Tymbion Lidocaine/epinephrine solution intervention 2: Device: Iontophoresis System (IPS) with Drug: Tymbion lidocaine/epinephrine solution
Intervention descriptions: intervention 1: The external ear canal will be filled with Tymbion drug solution intervention 2: The external ear canal will be filled with Tymbion drug solution. The Iontophoresis System (IPS) will be used to deliver current to the Tymbion solution to facilitate drug penetration into the tympanic membrane (TM) tissue to anesthetize (numb) the TM

Protocol documents:
Prot_000.pdf: 
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A PROSPECTIVE, MULTICENTER STUDY TO EVALUATE 
EFFECTIVENESS AND SAFETY OF LIDOCAINE IONTOPHORESIS AND 
TYMPANOSTOMY TUBE PLACEMENT USING THE TULA 
IONTOPHORESIS AND TUBE DELIVERY SYSTEMS FOR ADULTS IN 
AN OFFICE SETTING (ADEPT; ADult study to Evaluate Placement of 
tympanostomy Tubes in-office)
Study Products: 
•
TULA Iontophoresis System,
•
2% Lidocaine HCl/1:100,000 Epinephrine
•
and TULA Tube Delivery System
Study Phase: Pre-Pivotal 
Protocol #: CPR007003 
Revision: C 
IDE Number: G170002 
SPONSOR: 
Tusker Medical, Inc. 
155 Jefferson Drive, Suite 200 
Menlo Park, CA 94025 
USA 
MEDICAL MONITOR: 
This protocol contains confidential information for use by investigators participating in this 
study and should be maintained in a secure location. It should not be duplicated or made 
available for review by any unauthorized person or firm. 
NCT03119181


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A PROSPECTIVE, MULTICENTER STUDY TO EVALUATE 
EFFECTIVENESS AND SAFETY OF LIDOCAINE IONTOPHORESIS AND 
TYMPANOSTOMY TUBE PLACEMENT USING THE TULA 
IONTOPHORESIS AND TUBE DELIVERY SYSTEMS FOR ADULTS IN 
AN OFFICE SETTING (ADEPT; ADult study to Evaluate Placement of 
tympanostomy Tubes in-office) 
 
 
Protocol Number: CPR007003 
 
Approved By: 
 
______________________________________________  
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Date 
 
 
 
______________________________________________  
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Date 
 
 
 
______________________________________________  
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Date 
 
 
 
______________________________________________  
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Date 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
TABLE OF CONTENTS .................................................................................................................... 3 
1.0 
INVESTIGATORS .......................................................................................................................... 6 
2.0 
STATEMENT OF COMPLIANCE ....................................................................................................... 6 
3.0 
INVESTIGATOR SIGNATURE PAGE .................................................................................................. 7 
4.0 
LIST OF ABBREVIATIONS .............................................................................................................. 8 
5.0 
PROTOCOL SUMMARY ................................................................................................................. 9 
6.0 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE .............................................................. 17 
6.1. 
CLINICAL PROGRAM OVERVIEW .................................................................................................. 17 
6.2. 
CLINICAL AND TECHNOLOGY BACKGROUND .................................................................................. 17 
7.0 
STUDY DEVICES ........................................................................................................................ 19 
7.1. 
DEVICE DESCRIPTIONS............................................................................................................... 20 
7.1.1. IONTOPHORESIS SYSTEM ........................................................................................................... 20 
7.1.2. IONTOPHORESIS BASIC OPERATING PRINCIPLES ............................................................................. 25 
7.1.3. TUBE DELIVERY SYSTEM (TDS) ................................................................................................... 27 
8.0 
STUDY DRUG ........................................................................................................................... 28 
 
 
 
 
 
 ............................................... 28 
9.0 
TUSKER MEDICAL CLINICAL EXPERIENCE ....................................................................................... 30 
10.0 
RISK AND BENEFIT ANALYSIS ...................................................................................................... 30 
11.0 
STUDY DESIGN ......................................................................................................................... 30 
11.1. 
STUDY OBJECTIVE ..................................................................................................................... 30 
11.2. 
OVERALL STUDY DESIGN – GROUPS AND ENROLLMENT .................................................................. 31 
11.2.1. ENROLLMENT LIMITS ................................................................................................................ 32 
11.3. 
PRIMARY ENDPOINT RATIONALE ................................................................................................. 32 
11.4. 
STUDY POPULATION ................................................................................................................. 34 
11.4.1. DEFINITION OF ENROLLMENT ..................................................................................................... 34 
11.5. 
PRIMARY ENDPOINTS ................................................................................................................ 34 
11.6. 
SAFETY ENDPOINT .................................................................................................................... 36 
11.7. 
SECONDARY ENDPOINTS ............................................................................................................ 36 
 
 ........................................................................................................... 36 
 
 ............................................................................................. 36 
 ............................................................................................. 36 
11.9. 
INCLUSION CRITERIA ................................................................................................................. 37 
11.10. EXCLUSION CRITERIA................................................................................................................. 37 
12.0 
STUDY PROCEDURES ................................................................................................................. 39 
12.1. 
INVESTIGATOR TRAINING ........................................................................................................... 39 
12.2. 
EVALUATION METHODS ............................................................................................................ 39 
12.2.1. DIAGNOSIS (GROUP B) ............................................................................................................. 39 
12.2.2. CONCOMITANT MEDICATIONS .................................................................................................... 40 
12.2.3. CRANIAL NERVE PHYSICAL EXAM ................................................................................................ 40 
12.2.4. OTOSCOPY .............................................................................................................................. 40 
12.2.5. TYMPANOMETRY ...................................................................................................................... 41 
12.2.6. AUDIOMETRY .......................................................................................................................... 41 
12.2.7. ANESTHESIA EFFECTIVENESS ....................................................................................................... 41 
12.2.8. TOLERABILITY (VAS) ................................................................................................................. 42 
 .............................................................................................. 42 
12.2.10. VITAL SIGNS (GROUP B) ........................................................................................................... 43 


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12.3. 
SUBJECT RECRUITMENT AND INFORMED CONSENT......................................................................... 43 
12.4. 
SCREENING EVALUATIONS ......................................................................................................... 44 
12.5. 
PROCEDURE ............................................................................................................................ 44 
12.5.1. VITAL SIGNS (GROUP B) ............................................................................................................ 44 
12.5.2. OTOSCOPIC EXAMINATION AND EAR PREPARATION ....................................................................... 44 
12.5.3. EARSET SIZING ......................................................................................................................... 44 
12.5.4. ANESTHETIC SOLUTION PREPARATION ......................................................................................... 45 
12.5.5. EARSET PLACEMENT AND DRUG INSTILLATION .............................................................................. 45 
12.5.6. START OF IONTOPHORESIS ......................................................................................................... 45 
12.5.7. ANESTHETIC SOLUTION AND RETURN ELECTRODE PATCH REMOVAL ................................................. 46 
12.5.8. POST-IONTOPHORESIS ANESTHESIA EFFECTIVENESS (GROUP A) ....................................................... 46 
12.5.9. POST-IONTOPHORESIS ANESTHESIA EFFECTIVENESS (GROUP B) ....................................................... 47 
12.5.10. TYMPANOSTOMY TUBE PLACEMENT (GROUP B ONLY) ................................................................... 47 
12.5.11. CRANIAL NERVE EXAM ............................................................................................................. 47 
12.6. 
GROUP A FOLLOW-UP .............................................................................................................. 48 
12.7. 
GROUP B FOLLOW-UP .............................................................................................................. 48 
12.8. 
SUMMARY- STUDY EVALUATIONS, GROUP A ................................................................................ 49 
12.9. 
SUMMARY – STUDY EVALUATIONS, GROUP B ............................................................................... 49 
13.0 
ASSESSMENT OF SAFETY ............................................................................................................ 50 
13.1. 
ADVERSE EVENTS ..................................................................................................................... 50 
13.2. 
SERIOUS ADVERSE EVENTS ......................................................................................................... 51 
13.3. 
ADVERSE EVENT DEFINITIONS .................................................................................................... 51 
13.4. 
ADVERSE EVENT CLASSIFICATION ................................................................................................ 52 
13.5. 
SAFETY MONITORING ............................................................................................................... 54 
13.6. 
DEVICE MALFUNCTIONS ............................................................................................................ 54 
14.0 
STATISTICAL METHODS ............................................................................................................. 55 
14.1. 
SUBJECT DISPOSITION ............................................................................................................... 55 
14.2. 
GENERAL STATISTICAL METHODS ................................................................................................ 55 
14.3. 
GROUP A – STATISTICAL METHODS ............................................................................................. 56 
14.3.1. RANDOMIZATION & BLINDING ................................................................................................... 56 
14.3.2. ANALYSIS SETS ......................................................................................................................... 57 
14.3.2.1.MODIFIED INTENTION TO TREAT (MITT) ..................................................................................... 57 
14.3.2.2.PER PROTOCOL SET ................................................................................................................. 57 
14.3.2.3.SAFETY ANALYSIS SET .............................................................................................................. 57 
14.3.3. PRIMARY ENDPOINT ANALYSIS ................................................................................................... 57 
14.3.4. SAFETY ANALYSIS ..................................................................................................................... 58 
 .............................................................................................. 58 
14.4. 
GROUP B – STATISTICAL METHODS ............................................................................................. 58 
14.4.1. ANALYSIS SETS ......................................................................................................................... 58 
14.4.1.1.FULL ANALYSIS SET (FAS) ......................................................................................................... 58 
14.4.1.2.PER PROTOCOL SET ................................................................................................................. 58 
14.4.1.3 SAFETY ANALYSIS SET ............................................................................................................... 59 
14.4.2. PRIMARY ENDPOINT ANALYSIS ................................................................................................... 59 
14.4.3. SAFETY ANALYSIS ..................................................................................................................... 59 
 .............................................................................................. 60 
 
 
 
 
 
 ..................................................................... 61 
14.6. 
HANDLING DROP OUTS OR MISSING DATA ................................................................................... 62 
14.7. 
MULTIPLICITY ADJUSTMENT ....................................................................................................... 62 
15.0 
ETHICS/PROTECTION OF HUMAN SUBJECTS .................................................................................. 63 
15.1. 
SUBJECT CONFIDENTIALITY ......................................................................................................... 63 
16.0 
PREMATURE TERMINATION OR WITHDRAWAL .............................................................................. 63 


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16.1. 
SUBJECT STOPPING CRITERIA ...................................................................................................... 63 
 
 ........................................................................................................ 64 
17.0 
INVESTIGATOR RESPONSIBILITIES ................................................................................................. 65 
18.0 
SPONSOR ................................................................................................................................ 65 
19.0 
MONITORING .......................................................................................................................... 66 
20.0 
INVESTIGATIONAL PRODUCT ACCOUNTABILITY .............................................................................. 66 
21.0 
DEVIATIONS ............................................................................................................................ 66 
22.0 
DATA HANDLING AND RECORD KEEPING ...................................................................................... 67 
22.1. 
SOURCE DATA AND CASE REPORT FORMS .................................................................................... 67 
22.2. 
DATA QUALITY ASSURANCE ....................................................................................................... 67 
22.3. 
RECORD RETENTION ................................................................................................................. 67 
23.0 
PUBLICATION POLICY ................................................................................................................ 67 
24.0 
REFERENCES ............................................................................................................................ 68 
 
 
 
TABLES 
 
 ............................. 29 
Table 2. Schedule of Evaluations – Group A .......................................................................... 49 
Table 3. Schedule of Evaluations – Group B ........................................................................... 50 
Table 4. Table of Adverse Event Severity ............................................................................... 53 
Table 5. Table of Adverse Event Causality ............................................................................. 53 
Table 6. Table of Hearing Threshold Change (Worsening) Classification ............................. 54 
 
 
FIGURES 
 
. .......... 22 
 ................................................................................................. 23 
Figure 3. Return Electrode Patch ............................................................................................. 24 
Figure 4. Ear Plug Sizers ......................................................................................................... 24 
Figure 5. Current Ramp Profile ............................................................................................... 26 
Figure 6. Schematic of Iontophoresis of the TM ..................................................................... 26 
Figure 7. Tusker Medical Tympanostomy Tube ...................................................................... 27 
Figure 8. Tube Delivery System .............................................................................................. 27 
Figure 9. Visual Analogue Scale (not shown to scale) ............................................................ 42 
 ....................................................................................... 42 
 
 
 


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1.0  INVESTIGATORS 
A list of Investigators is provided with the Investigator’s Information and will be submitted 
to the FDA and IRB. 
 
 
Statements of Qualifications: 
Qualifications of investigators are provided in the Investigator Information and will be 
submitted to the FDA and IRB. 
 
2.0 STATEMENT OF COMPLIANCE 
This study will be conducted in accordance with any specific provisions of the associated 
Institutional Review Board(s) (IRBs) and 21 CFR Parts 812 and 312. This study will be 
conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki and that are consistent with Good Clinical Practice (GCP), ISO 14155 and the 
applicable national and regional regulatory requirements. Specifically, this study will be 
guided by the ethical principles of The Belmont Report, the Declaration of Helsinki, and 
the International Conference for Harmonization Good Clinical Practice (ICH-GCP).  
 
 


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3.0  INVESTIGATOR SIGNATURE PAGE 
I acknowledge receipt of protocol and confirm I have read and understood its contents and 
agree to fulfill my obligations as described herein. I will ensure that the study is conducted 
in compliance with the protocol and all applicable regulatory requirements. 
 
 
 
_______________________________________________________  
INVESTIGATOR (Print Name) 
 
 
_______________________________________________________ 
INSTITUTION 
 
 
_______________________________________________________ 
ADDRESS 
 
 
_______________________________________________________ 
SIGNATURE 
 
 
_______________________________________________________ 
DATE (DD/MMM/YYYY) 
 
 


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4.0  LIST OF ABBREVIATIONS  
 
 
 
AE  
 
 
Adverse Event 
AOM 
 
 
Acute Otitis Media 
CFR 
 
 
Code of Federal Regulations 
CRF 
 
 
Case Report Form 
CTA  
 
 
Clinical Trial Agreement 
dB  
 
 
Decibels 
DC 
 
 
Direct Current 
DIPS 
 
 
Device Initiated Pause Sequence 
EMLA 
 
 
Eutectic Mixture of Lidocaine HCl and Prilocaine 
ENT 
 
 
Ear, Nose and Throat 
FAS 
 
 
Full Analysis Set 
FDA 
 
 
Food and Drug Administration 
FPS-R 
 
 
Faces Pain Scale- Revised 
GCP 
 
 
Good Clinical Practice 
HCl 
 
 
Hydrochloride 
ICH 
 
 
International Conference for Harmonization 
IDE 
 
 
Investigational Device Exemption 
IFU 
 
 
Instructions For Use 
IND 
 
 
Investigational New Drug Application 
IO  
 
 
In Office 
IPS 
 
 
Iontophoresis System 
IRB 
 
 
Institutional Review Board 
ISO 
 
 
International Organization for Standardization 
LCD 
 
 
Liquid-Crystal Display 
MedRA 
 
 
Medical Dictionary for Regulatory Activities 
mITT 
 
 
Modified Intent to Treat 
MTT 
 
 
Myringotomy with Tympanostomy Tube 
NSR 
 
 
Non-Significant Risk 
OME 
 
 
Otitis Media with Effusion 
OR 
 
 
Operating Room 
PSA 
 
 
Pressure-Sensitive Adhesive 
SAE 
 
 
Serious Adverse Event 
SD  
 
 
Standard Deviation  
TDS 
 
 
Tube Delivery System 
TM 
 
 
Tympanic Membrane 
TT  
 
 
Tympanostomy Tube 
UADE 
 
 
Unanticipated Adverse Device Effect 
VAS 
 
 
Visual Analogue Scale 
 
 






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audiometry will be conducted.  If there are unresolved device, procedure 
or drug-related adverse events at the 3-day follow-up visit, a 12-day 
follow-up visit is required. 
Group B will consist of 30 evaluable adults age 18 years or greater who 
require unilateral or bilateral tube insertion enrolled at up to 9 centers in 
the US. Otologic examination, cranial nerve physical exam, tympanometry 
and audiometry will be conducted at the screening visit.     
Group B subjects will receive active lidocaine iontophoresis and will have 
tubes placed using the TDS in all ears indicated for tube placement.  The 
subject will rate the pain upon TDS tube insertion using the VAS, and the 
pain score will be compared to a performance goal. 
 
 
 
Vital signs (diastolic and systolic blood pressure, heart rate, 
respiratory rate and pulse oximetry) will be monitored prior to and 
periodically up to 1 hour following iontophoresis. A follow-up at 3 weeks 
is required for all subjects, at which point otologic examination, cranial 
nerve physical exam, tympanometry and audiometry will be conducted. 
 
 












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6.0  BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
6.1.  Clinical Program Overview 
Tusker Medical has developed a suite of technologies designed to enable in-office 
placement of tympanostomy tubes in pediatric and adult patients. This protocol 
(CPR007003) describes two groups of adult subjects, each designed to demonstrate a 
particular aspect of the investigational technology.  
 
 
 
 
 
 
Although this study is conducted in adult subjects and the investigational technology will 
ultimately be available for both adult and pediatric patients, it is anticipated that the 
majority of use will be in the pediatric population.  Therefore, Section 6.2 is focused on 
the ultimate use of the product in the pediatric population. 
 
6.2. Clinical and Technology Background 
 
Otitis media (inflammation of the middle ear) is the most frequent diagnosis in sick children 
visiting pediatrician offices. Seventy-five percent of children experience at least one 
episode of otitis media by their third year.3  
 
Otitis media has several variations, including acute otitis media (AOM) and otitis media 
with effusion (OME). AOM is characterized by acute signs and symptoms of middle ear 
inflammation or infection.  OME is characterized by the presence of fluid in the middle ear 
with or without signs or symptoms of acute ear infection.  The highest incidence of AOM 
occurs between six and 24 months of age and declines until a small reversal is seen between 
five and six years of age, at the time of school entry.4 There tends to be a higher incidence 
of OME in younger than in older children, because the Eustachian tube in younger children 
is shorter, narrower, and more horizontal and the immune system is less developed 
compared to older children or adults. There is also increased incidence of OME associated 
with craniofacial anomalies, cleft palate, and Down syndrome.  Middle ear effusion can 
result in temporary conductive hearing loss and negatively impact a child’s cognitive, 
language, and emotional development.   
 
More than 750,000 tympanostomy tube procedures are performed in children younger than 
age 18 annually in the US to address recurrent AOM or OME, making it one of the most 
common surgical procedures performed in children.5 By age 3, almost 7% of all children 
will have tympanostomy tubes.1 Over 75% of tympanostomy tube procedures in the US are 
performed for children 12 years or younger, with 58% of tube procedures for children less 
than 5 years of age.5  Over 95% of tympanostomy tube insertion procedures in children are 
performed in the operating room (OR) under general anesthesia.5  
 
The typical Myringotomy with Tympanostomy Tube placement (MTT) procedure in a child 
involves the following sequence of events: 


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• The child fasts from the evening before the procedure and is brought to the 
hospital or ambulatory surgery center. 
• Premedication with oral midazolam may be provided to calm the child prior to 
parental separation.6 
• After general anesthesia is attained, prophylactic analgesia to address post-
operative pain such as rectal acetaminophen or intranasal fentanyl is typically 
provided.7 
• Cerumen clearance is performed. 
• Using a myringotomy blade, an adequately sized myringotomy incision is then 
made, typically in the anteroinferior portion of the tympanic membrane.8,9  
• Fluid may be removed from the middle ear space using suction. 
• Using alligator forceps, the tympanostomy tube is manipulated and tucked into 
the myringotomy incision. 
• Minor adjustments are then often performed using standard otologic 
microinstruments, such as a Rosen needle or alligator forceps, to achieve 
optimal tube position.10  
• Multiple attempts to place the tube may be required in a considerable number 
of cases.8  
 
In adult patients and older children, tympanostomy tubes can be placed in an office setting 
using a variety of local anesthesia options although none are indicated for anesthesia of the 
ear drum. Phenol (carbolic acid) is often used to cause a partial thickness chemical burn 
with tissue necrosis, which leads to localized anesthesia of the TM.11 Other anesthetics, 
such as EMLA cream (Eutectic Mixture of Local Anesthetics, lidocaine 2.5% and 
prilocaine 2.5%), lidocaine HCl injections and Bonain’s Solution (cocaine hydrochloride, 
menthol, phenol) and tetracaine injections are used less frequently.12,13,14  None of the local 
anesthetics employed in adults are regularly used with small children, as they are all 
associated with discomfort or a lengthy onset incompatible with pediatric use.  
 
There are several potential advantages to providing otolaryngologists, or Ear, Nose and 
Throat (ENT) surgeons, with technology that enables in-office tube placement in pediatric 
patients. The perioperative risks associated with the general anesthesia required for tube 
placement in the OR can be avoided with an office-based procedure. General anesthetic 
complications occur at measurable rates ranging between 12.6% and 18% in tube 
procedures in children.15,16 Although serious adverse effects of general anesthesia during 
tube procedures are uncommon, they can be severe including laryngospasm, airway 
obstruction, desaturation, dysrhythmia and post-operative vomiting requiring treatment. 
 
In addition, there is an increasing interest in gaining a better understanding of the potential 
for neurodevelopmental impact of general anesthesia in small children.  A growing body 
of literature suggests a linkage between general anesthesia exposure and 
neurodevelopmental impact, though it remains difficult to separate the post-general 
anesthesia outcomes from the underlying condition for which the child underwent surgery. 
One study showed that children who received general anesthesia before age 3 years were 
approximately 1.9 times as likely as controls to show language disability and 1.7 times as 




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the prior generation of the device. 
 
 
 
 
 
 
 
 
 
Tusker Medical, Inc. has a Tube Delivery System intended to provide a means to create a 
myringotomy with insertion of a preloaded tympanostomy tube. The design and operation 
of the TDS is intended to standardize the surgical approach to tympanostomy tube 
placement whereby upon actuation of the TDS, a myringotomy is created and a Tusker 
Medical tympanostomy tube is placed nearly simultaneously (within 500 ms). The TDS 
device combines myringotomy creation and tube insertion into one straightforward 
procedure step, thus avoiding the need to pass an exposed surgical blade though the ear 
canal of an awake and mobile patient.   
 
 
 
 
 
 
7.1. Device Descriptions 
7.1.1. 
Iontophoresis System 
Iontophoresis uses low-level electric current to direct movement of drug ions into tissue 
through skin or mucosal surfaces. 
 
 
 The IPS employs a low-level electric current to transport 
the ionic drug, and may be performed unilaterally or bilaterally. The IPS is battery-powered 
and delivers 6.4mA-minutes of charge at a current of 0.8 mA (maximum) to each channel.  
 
The IPS is a single use device and consists of three components: an Iontophoresis Control 
Unit, Iontophoresis Earsets and a Return Electrode Patch. For bilateral drug delivery, two 
Iontophoresis Earsets are required. Accessories to the Iontophoresis System include a 
Syringe and Earset Sizers. All components of the IPS are provided non-sterile and no 
sterilization is required. All patient contact materials have been assessed for 
biocompatibility per ISO 10993. Iontophoresis with the IPS may be performed unilaterally 
or bilaterally, and bilateral iontophoresis may be performed either sequentially or 
simultaneously. 
 
• The Earset Sizers are used to determine the Earset size that best fits the patient’s 
anatomy. They are color-coded to correspond to each Earset size. Consecutive sizes are 
mounted at each end of a handle and labeled with a size number (Size 1 through Size 
6). They are a reusable accessory required to determine the Earset size for the ear canal 
requiring treatment. 


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• The Earset includes an Ear Plug with Pressure-Sensitive Adhesive (PSA) attached to a 
handle, an integrated fill system, an electrical connector, and an integrated ear electrode 
through which electrical current is delivered to the drug solution. The integrated fill 
system allows for the administration of drug solution with the electrode in situ for the 
initial fill of the external ear canal and for the intra-procedure delivery of additional 
drug solution to the external ear canal, as needed. Multiple Earset sizes are available to 
accommodate variation in patient anatomy and are color-coded to correspond to the 
Earset Sizers. The range of ear plug sizes is appropriate for both pediatric and adult 
patients. 
 
• The Control Unit provides two independent channels of electrical current to the 
solution in the ear canal and to a single shared return electrode patch. The Control Unit 
monitors and delivers a fixed amount of charge and alerts the operator when current 
delivery is complete.  
 
• The Return Electrode Patch attaches to the patient’s skin at a location remote from 
the ears to complete the electrical circuit and is connected to the Earset and Control 
Unit via the return electrode snap.  
 
• The Syringe is a single use device that allows for administration of drug solution 
through the Earset into the ear canal. 
 
Iontophoresis Control Unit 
 
 
 
 
The Control Unit provides two independent 
channels of electrical current. It is connected to one or two Earsets and the Return Electrode 
Patch via the electrical connectors and return electrode snap, respectively.  The Control 
Unit can deliver current to a patient’s left and right ears sequentially or simultaneously, if 
desired. The Control Unit includes embedded software that delivers and regulates both 
current and accumulated charge and alerts the operator when current delivery is complete. 
 
  
 
The user interface with the Control Unit consists of two push buttons and a visual indicator 
of cycle progress (progress bars).  Each push button is used to independently operate one 
Earset. Each push button can start, pause or resume current to one Earset. Push buttons are 
color coded (Yellow and Blue) to identify the Earset side they control. The progress bars  
are used to monitor iontophoresis progress and alert the operator of various device states. 
 
 
 
If the Reduce feature is used by the operator, the device tracks overall charge, ensuring 
total charge/dose delivered remains the same as the prior generation of the device.   




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The Earset also includes an integrated ear electrode. The integrated ear electrode is used to 
deliver positive DC electrical current to the administered drug. 
 
 
  
 
 
 
 
 
Return Electrode Patch 
 
The Return Electrode Patch (Return Electrode) shown in Figure 3, attaches to the patient’s 
skin, generally on the arm or back, to complete the electrical circuit. The Return Electrode 
contains a hydrogel, which contacts and adheres to the patient’s skin. The Return Electrode 
acts as a cathode. The Return Electrode is connected to the System Cable of the Control 
Unit.  














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9.0   TUSKER MEDICAL CLINICAL EXPERIENCE  
 
 
 
 
 
 
 
 
 
 
The Investigator’s Brochure (CIB007001) includes a complete summary of the prior 
clinical data and the specific device generations used for each study. 
 
10.0 
RISK AND BENEFIT ANALYSIS 
A description of risks and an analysis of risk versus benefit for subjects undergoing 
iontophoresis with tube placement (Group B) is presented in the Investigator’s Brochure 
CIB007001.  Group A subjects consist of healthy adult volunteers.  There are no benefits 
to healthy volunteers. However, the information collected will provide a foundation for the 
development of future applications and technology. 
 
11.0 
 STUDY DESIGN 
11.1. 
Study Objective 
Prior clinical trial experience has provided preliminary safety and effectiveness of in-office 
tympanostomy tube placement in children using the Tusker Medical TULA Iontophoresis 
and Tube Delivery Systems. The objectives of this study are two-fold: 
 
1) to determine if active lidocaine iontophoresis is superior to sham lidocaine 
iontophoresis in providing anesthesia to the tympanic membrane, and  
 
2) to evaluate tolerability and safety of tympanostomy tube (TT) placement in adults 
following local anesthesia in a physician’s clinic setting. 
 
This study will consist of two independent Groups (Group A and Group B).  Each group 
has its own primary endpoint, both of which must pass the statistical test for the overall 
study to be considered successful and to meet the study objectives. In addition, safety will 
be evaluated by review of the occurrence of adverse events. 
 
The data from this study will provide evidence that the investigational system will provide 
anesthesia sufficiently effective for the placement of tympanostomy tubes.  
 
 
 
 


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11.2. 
Overall Study Design – Groups and Enrollment 
This study is a prospective, multicenter study to evaluate effectiveness and safety of 
lidocaine iontophoresis and tympanostomy tube placement using the TULA iontophoresis 
and tube delivery systems for adults in an office setting. 
 
This study will consist of two independent Groups (Group A and Group B).  Each Group 
has its own primary endpoint, each of which must pass the statistical test for the overall 
study to be considered successful.  The two Groups may be enrolled in parallel, and 
investigational sites may enroll subjects in Group A alone, Group B alone, or both Groups. 
 
Group A will consist of 40 healthy adult subjects aged 18-50 with evaluable data, enrolled 
at two investigational centers in the US. Otologic examination, cranial nerve physical 
exam, tympanometry and audiometry will be conducted at the screening visit.     
 
Group A subjects will be randomized to receive unilateral treatment (1 ear) with either 
active lidocaine iontophoresis or sham lidocaine iontophoresis.  The sham iontophoresis 
procedure will be identical to the active lidocaine iontophoresis, with the exception that 
the iontophoresis channel will not be activated (ie, the same drug solution will be applied 
to ears in both arms). 
 
  
 
After the completion of the iontophoresis, the tympanic membrane will be touched with a 
dull otologic probe to test anesthesia effectiveness.   The touch to the TM will slightly 
deflect the TM and allow for an assessment of anesthesia effectiveness. The touch is 
referred to as a ‘tap’ throughout the protocol. 
 
 
 
The subject will rate the level of pain using the Visual Analogue Scale (VAS) 
after the tap.  
 
 Investigators and subjects will be blinded to treatment 
assignment. 
 
A follow-up at 3 days post-procedure is required for all subjects, at which point otologic 
examination, cranial nerve exam, tympanometry and audiometry will be conducted.  If 
there are unresolved device, procedure or drug-related adverse events at the 3-day follow-
up visit, a 12-day follow-up visit is required. 
 
Group B will consist of 30 adults 18 years or older who require unilateral or bilateral tube 
insertion, enrolled at up to 9 centers in the US.  Otologic examination, cranial nerve 
physical exam, tympanometry and audiometry will be conducted at the screening visit.     
 
Group B subjects will receive active lidocaine iontophoresis and TDS-mediated tube 
placement in all ears that require tube insertion.  The VAS score will be collected after 
any manipulations required to place the tube so that the pain score fully reflects the 
activities required to place the tube. VAS score will be collected for each ear undergoing 
tube placement. If a subject discontinues iontophoresis or the procedure prior to tube 
placement with the TDS, a VAS score will be collected for the attempted procedure. The 
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Vital signs (diastolic and systolic blood pressure, heart rate, respiratory rate and pulse 
oximetry) will be monitored 15 minutes and immediately prior to iontophoresis, 
immediately following the iontophoresis, following tube placement, 30 minutes and 60 
minutes after completion of iontophoresis for all Group B subjects. 
 
A follow-up at 3 weeks is required for all subjects, at which point an otologic examination, 
cranial nerve exam, tympanometry and audiometry will be conducted. 
 
11.2.1.  Enrollment Limits 
Group A: Group A consists of 2 sites. Each site may enroll no greater than 70% of Group 
A subjects.  
 
Group B: Group B consists of up to 9 sites. Each site may enroll no greater than 30% of 
Group B subjects.  
 
11.3. 
Primary Endpoint Rationale 
Group A: Anesthesia Effectiveness (Subject-Reported) 
 
In Group A, active lidocaine iontophoresis will be compared to sham lidocaine 
iontophoresis (ie, lidocaine in the ear canal but without activating the iontophoresis unit for 
that channel).  After iontophoresis/sham treatment is complete, the subject will use the VAS 
to rate the pain associated with a single tympanic membrane tap using a standardized blunt 
otologic probe. The VAS was selected because it is a validated self-report pain instrument 
commonly used in research settings with adults (reviewed in Jensen and Karoly).34  The 
VAS is validated for use in subjects 8 years of age and older (reviewed in Stinson et al 
(2006).35  The VAS consists of a 10 centimeter (cm) line with a statement at each end 
representing the extreme limits of pain intensity (“No pain” to “Worst possible pain”).  The 
subject reports their pain intensity by making a mark along the line and the line is measured 
to convert the subject response to numeric score (0-10 in centimeters). 
 
 
 
 




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cut points for pain severity as no pain at 0 to 4 mm, mild pain 5 to 44 mm, moderate pain 
45 to 74 mm and severe pain 75 to 100mm. Altogether, the literature reports show 
remarkable consistency for the experimentally-determined cut point between mild and 
moderate pain. 
 
Prior TULA in office tube delivery study results indicate that tolerability scores are 
anticipated to be in the mild range. Therefore, it is reasonable to set a performance goal to 
be superior to (less painful than) moderate pain. Using the VAS, Tusker will demonstrate 
superiority to a score of 4.5cm (or 45mm), based on Jensen’s determined cut point of 45mm 
for adult VAS scores, showing that the pain associated with in-office tube insertion in adult 
subjects is mild.   
 
11.4. 
Study Population 
Group A will consist of 40 healthy adult volunteers and Group B will consist of 30 adults 
indicated for tympanostomy tubes in one or both ears. The study may enroll up to 85 
subjects to achieve 40 subjects with evaluable data in Group A and 30 subjects with 
evaluable data in Group B, allowing for approximately 15 screen failure or withdrawn 
subjects. 
 
11.4.1. Definition of Enrollment 
All subjects who consent for participation in the study are considered enrolled.  Subjects 
who do not meet eligibility criteria are considered screen failures.  Section 14.0 Statistical 
Methods provides further definition of subjects included in the analysis sets. 
 
11.5. 
Primary Endpoints 
There are two primary endpoints for the study, one for Group A and one for Group B.  Both 
primary endpoints must be achieved for the trial to be considered successful.  
 
Primary endpoint for Group A: 
 
Anesthesia Effectiveness: subject-reported pain score elicited by tympanic membrane tap 
following active lidocaine iontophoresis compared to sham lidocaine iontophoresis using 
the VAS.    
 
Each Group A subject will each have a VAS score.   If a subject in Group A discontinues 
iontophoresis prior to the TM tap assessment or declines the TM tap assessment, the subject 
will provide a pain score for the attempted procedure and will be included in the analysis 
of the primary endpoint. 
 
 
 
 
Reasons for discontinuation will be documented and presented in the clinical 
study report.   
 
Randomization will assign subjects to either unilateral active lidocaine iontophoresis or 
unilateral sham lidocaine iontophoresis treatment. Both the subject and the investigator 


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performing the taps will be blinded as to treatment assignment. Blinding is further 
described in Sections 12.5.5 and 14.3.1. 
 
A single tap will be performed on the treated (or sham-treated) ear using a standardized 
dull otologic probe on the anterior part of the tympanic membrane.  
 
   
 
Primary endpoint for Group B:  
 
Tube Placement Tolerability: Subject-reported pain score following TDS tube 
placement using the VAS. 
 
Group B subjects will each have a single subject-level VAS score that reflects the pain 
associated with tube insertion; if both ears are treated the highest score of the two ears will 
serve as the subject-level score.  The statistical test for the primary endpoint is a hypothesis 
test comparing mean VAS score to a performance goal of 4.5, as described in Section 11.3.  
 
Group B subjects may require unilateral or bilateral tubes and will receive active lidocaine 
iontophoresis and tube placement using the TDS in each ear that requires a tube insertion.   
 
 
 
 
 
 
 
 
 
 
 
 
   
 
The VAS score will be collected after any manipulations required to place the tube so that 
the pain score fully reflects the activities required to place the tube. A VAS score will be 
reported for each ear undergoing tube placement, and the highest (worst) pain reported by 
the subject will be used as the unit of analysis. 
 
If a subject in Group B discontinues iontophoresis or tube placement, the subject will 
provide a VAS pain score for the attempted procedure. 
 
 
 
 
 
 
 
 
 
Reasons for discontinuation will be documented and presented in the 
clinical study report. 
 
 


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11.6. 
Safety Endpoint 
Safety: The occurrence of all adverse events, by subject. The totality of the safety data 
will be summarized and presented. Safety events will be reported for all subjects in which 
the lidocaine solution was introduced into the ear (see Section 14.2.3), and will be 
reported for the following time intervals: 
 
• Events occurring during the procedure visit 
• Events occurring between the procedure through the subject’s final follow-up visit 
 
Safety data will be presented separately as follows: 
 
• Group A 
• Group B 
 
11.7.    Secondary Endpoints 
There are no formal tests of hypotheses for secondary endpoints in either Group A or Group B. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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11.9. 
 Inclusion Criteria  
Group A: At least one ear must meet ear-specific eligibility criteria. 
Group B: Each ear indicated for tube placement must meet ear-specific eligibility criteria. 
 
Group A:  
 
1. 
Healthy adults, 18-50 years old at time of consent  
2. 
Subject is able and willing to comply with the protocol and attend all study visits 
3. 
Subject is able and willing to provide informed consent 
4. 
Subjects with air conduction hearing thresholds of 25 dB HL or better at standard 
frequencies up to 2000 Hz, and 45 dB or better at 4000 Hz. 
5. 
Subject is able to read and understand English 
 
 
Group B:  
 
1. 
Adults at least 18 years of age at time of consent 
2. 
Indication for tympanostomy tube insertion per Clinical Practice Guideline,40 or 
indicated for tympanostomy tube insertion tube insertion due to barotrauma or 
Eustachian tube dysfunction per AAO-HNS Clinical Indicators41  
3. 
Subject is able and willing to comply with the protocol and attend all study visits 
4. 
Subject is able and willing to provide informed consent. 
5. 
Subject is able to read and understand English. 
 
11.10. 
 Exclusion Criteria 
Group A: 
 
1. 
Pregnant or lactating females. 
2. 
Prior ear iontophoresis procedure experience. 
3. 
Subjects with conductive hearing loss. 
4. 
Subjects with history of sensitivity or allergic reaction to lidocaine HCl, tetracaine, 
epinephrine, or any hypersensitivity to local anesthetics of the amide type, or any 
component* of the anesthetic drug formulation.  
 
*Subjects with a known hypersensitivity to methylparaben and/or propylparaben 
(preservatives used in lidocaine HCl formulations), or to their metabolite para amino 
benzoic acid (PABA), or other components including potassium metabisulfite, sodium 
metabisulfite, ededate disodium or citric acid. 
 
5. 
Familial history of insensitivity to lidocaine or other local anesthetics of the amide 
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6. 
Significantly atrophic, retracted, bimeric, monomeric or atelectatic tympanic 
membrane. 
7. 
Perforated tympanic membrane. 
8. 
Subjects with known history of ear surgery or TM condition that has the potential to 
affect the sensitivity of the TM (ex. prior tympanostomy tube insertion) 
9. 
Otitis externa. 
10. 
Damaged/denuded skin in the auditory canal. 
11. 
Subjects with electrically sensitive support systems (pacemakers, defibrillators, etc.). 
12. 
Cerumen impaction resulting in a significant amount of cleaning required to visualize 
the tympanic membrane. 
13. 
Evidence of Otitis Media at day of procedure, or within the past three (3) months prior 
to procedure.  
14. 
Other conditions that would preclude performing the study procedure including ear 
plug incompatibility. 
15. 
Health conditions that, in the opinion of the investigator, would present undue risk to 
the subject, based on device/anesthetic drug product label warnings and precautions.  
 
Group B: 
 
1. 
Significantly atrophic, retracted or retraction pocket at location of tube placement, 
bimeric, monomeric or atelectatic tympanic membrane. 
2. 
Perforated tympanic membrane. 
3. 
Otitis externa. 
4. 
Hemotympanum. 
5. 
Damaged/denuded skin in the auditory canal. 
6. 
Cerumen impaction resulting in a significant amount of cleaning required to visualize 
the tympanic membrane potentially causing abrasion or irritation to the external ear 
canal. 
7. 
Notable ear discomfort experienced during audiologic or otoscopic examination. 
8. 
Anatomy that precludes sufficient visualization of and access to the tympanic 
membrane. 
9. 
Anatomy that necessitates tympanostomy tube placement in the posterior half of the 
tympanic membrane). 
 
General Exclusion Criteria 
 
10. 
Pregnant or lactating females. 
11. 
History of sensitivity or allergic reaction to lidocaine HCl, tetracaine, epinephrine, or 
any hypersensitivity to local anesthetics of the amide type, or any component* of the 
anesthetic drug formulation. 
 
*Subjects with a known hypersensitivity to methylparaben and/or propylparaben 
(preservatives used in lidocaine HCl formulations), or to their metabolite para amino 
benzoic acid (PABA), or other components including potassium metabisulfite, 
sodium metabisulfite, ededate disodium or citric acid. 
 
12. 
Familial history of insensitivity to lidocaine or other local anesthetics of the amide 
type.  
13. 
Electrically sensitive medical support systems (eg, pacemakers, defibrillators, 
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14. 
Other conditions that would preclude performing the study procedure including 
iontophoresis system ear plug incompatibility. 
15. 
Health conditions that, in the opinion of the investigator, would present undue risk to 
the subject, based on device/anesthetic drug product label warnings and precautions 
 
If a previously-determined eligible subject presents on the procedure day with a change in 
condition, such as an acutely infected ear, the investigator may use clinical judgment to 
determine whether the condition as presented precludes performing the study procedure 
(Group B Exclusion 14). The physician also has the option to re-schedule the procedure if 
the condition is transient. 
 
12.0 STUDY PROCEDURES 
12.1. 
Investigator Training  
Investigators will be asked to refer to the drug package insert, device Instructions For Use 
(IFU) and the Investigator’s Brochure (CIB007001) for risks related to procedure, drug and 
device. The Investigators will be trained on use of the Iontophoresis and Tube Delivery 
Systems using a model system. 
 
12.2. 
Evaluation Methods 
12.2.1. Diagnosis (Group B) 
Eligible subjects will be indicated for tympanostomy tube placement in alignment with the 
Clinical Practice Guideline.1  The Clinical Practice Guideline for tympanostomy tubes in 
children was developed by a multidisciplinary panel, to provide clinicians with evidence-
based recommendations on patient selection and surgical indications for and management 
of tympanostomy tubes in children.  
 
In addition to indications aligned with the Clinical Practice Guideline for children, the adult 
subjects in Group B with barotrauma or Eustachian tube dysfunction may also be indicated 
for tube placement per AAO-HNS Clinical Indicators (2010).2Error! Bookmark not defined. 
 
According to the Clinical Practice Guideline, the decision to perform unilateral or bilateral 
tympanostomy tube insertion when unilateral OME is present should be based on caregiver 
preference [to accept or decline the risk of a second surgical procedure] and the likelihood 
of persistent OME developing in the opposite ear. For AOM with presence of effusion, the 
Guideline recommends bilateral TT placement for unilateral or bilateral disease. With the 
current care paradigm, a physician may perform bilateral tube placement for a unilateral 
condition to avoid the risk of multiple OR procedures and general anesthesia exposures if 
the second ear becomes affected.  Since this study procedure is conducted in-office, it is 
proposed that the decision to perform unilateral or bilateral TT placement for AOM with 
effusion be based on subject preference and physician clinical judgment regarding the 
likelihood of disease developing in the opposite ear, similar to the Guideline 
recommendation for chronic OME.   
 


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The indications for tube placement have been clarified (as noted in italics) in instances 
where unilateral placement may be deemed appropriate by the physician and acceptable by 
the subject. The clinical indications for tube placement for children include:  
 
• Bilateral TT insertion for bilateral otitis media with effusion (OME) for 3 months or 
longer (chronic OME) and documented hearing difficulties; 
• Unilateral or bilateral TT insertion for unilateral or bilateral OME, respectively, for 3 
months or longer (chronic OME) and symptoms that are likely attributable to OME 
that include, but are not limited to, vestibular problems, poor school performance, 
behavioral problems, ear discomfort, or reduced quality of life; 
• Unilateral or bilateral TT insertion for recurrent acute otitis media (AOM) with 
unilateral or bilateral middle ear effusion at the time of assessment for tube candidacy, 
where recurrent AOM is defined as three or more AOM episodes in the past 6 months 
or at least 4 AOM episodes in the past 12 months with at least 1 in the past 6 months. 
 
In this study, the subject will be informed of the risk of subsequent OME or AOM in the 
contralateral ear and the potential need for a second tube insertion procedure should this 
occur. Prior to procedure, the Investigator must document which ears are intended for in-
office tube placement. 
 
12.2.2. Concomitant Medications 
All prior and concomitant medications will be recorded. Prior medications will include all 
prescription and over-the-counter medications taken up to 28 days before procedure. All 
concomitant medications, and changes to medications, will be recorded during each 
subject’s study enrollment period. Medications may be prescribed based on Investigator’s 
discretion, except for drugs or devices under investigation through a different protocol.  
 
12.2.3. Cranial Nerve Physical Exam 
A standard cranial nerve physical exam will be employed at screening, post-procedure and 
at the follow-up visit to identify any potential adverse effects. 
 
 
 
 
Any abnormalities will be recorded at screening and at the follow-up visit and the 
subject will be assessed for any adverse events. 
 
 
 
12.2.4. Otoscopy 
An otoscopic exam will be conducted for both ears in all subjects for all study visits.  The 
otoscopic examination will be used to visually examine the condition of the external ear 
canal and TM. Routine ear cleaning may be conducted only to the extent necessary to 
ensure the tympanic membrane and ear canal are free from matter that may interfere with 
iontophoretic delivery and to ensure visualization of the tympanic membrane.  
 
The exam will be used to confirm eligibility and to assess the ear canal and TM for changes 
or adverse effects. Presence or absence of middle ear effusion will be assessed. In addition, 


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appearance of the myringotomy wound and patency of the tympanostomy tube (Group B 
only) will be evaluated at the follow-up visit. Tube functional patency will be determined 
through clinical assessments including otoscopic examination and tympanometry. 
 
The screening otoscopic exam may be conducted up to 28 days prior to procedure and will 
be conducted for both ears of all subjects to determine eligibility and ears selected (Group 
A) or indicated (Group B) for treatment. Otoscopic examination is considered standard of 
care for the Group B patient population and may be obtained prior to study informed 
consent as a screening assessment within 28 days prior to procedure. Otoscopic images 
may be collected prior to and following iontophoresis. 
 
12.2.5. Tympanometry 
Standard tympanometry for both ears will be employed to assess TM function at screening 
(within 28 days prior to procedure) and at the follow-up visit for all subjects. 
Tympanometry data recorded will include tympanogram type, ear canal volume, peak 
pressure and static acoustic immittance and gradient as an objective measure of tube 
patency and middle ear status.  If adequate tympanometer seal or a valid tympanogram 
cannot be achieved for screening tympanometry evaluation (eligible ears for Group A 
subjects and indicated ears for Group B subjects), the subject will be considered a screening 
failure, and will not be eligible for the study. Tympanometry is considered standard of care 
for the Group B patient population and may be obtained prior to study informed consent as 
a screening assessment within 28 days prior to procedure.  Tympanostomy tube functional 
patency will be determined through clinical assessments including otoscopic examination 
and tympanometry. 
 
12.2.6. Audiometry 
Audiometry will be employed to evaluate hearing status and TM function for both ears at 
screening (within 28 days prior to procedure) and at the post-procedure follow-up visit for 
all subjects. Threshold testing will be conducted for each ear using air conduction and bone 
conduction at a minimum of 500, 1000, 2000 and 4000 Hz.  
 
Audiometry is considered standard of care for the Group B patient population and may be 
obtained prior to study informed consent as a screening assessment within 28 days prior to 
procedure. 
 
12.2.7. Anesthesia Effectiveness  
Following iontophoresis for Group A, the Investigator will gently tap the TM once with a 
standardized dull otologic instrument. The tap will occur on the anterior half of the TM at 
the location where the tympanostomy tube would theoretically be placed.  The Investigator 
will assess whether the TM is adequately anesthetized for a hypothetical tympanostomy 
tube placement based on subject response to the TM tap which is recorded via VAS.  
 
 
 
 
For Group B, the Investigator will inspect the ear canal and TM following iontophoresis. 
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12.2.10. 
Vital Signs (Group B) 
Vital signs (diastolic and systolic blood pressure, heart rate, respiratory rate and pulse 
oximetry) measurements will used to evaluate baseline and peri-procedural vital signs to 
assess for any systemic effects of administered drug. Vital signs measurements will be 
recorded 15 minutes and immediately prior to iontophoresis, immediately following 
iontophoresis, following tube placement and at 30 and 60 minutes after completion of 
iontophoresis. Subjects who experience significant changes in vital signs (30% or greater 
compared to baseline) will undergo continued vital sign assessment until the vital sign 
measurements have returned to baseline (ie, beyond the 1-hour post-procedure evaluation 
period). Additionally, significant changes (30% or greater compared to baseline) will be 
considered adverse events.  
 
12.3. 
Subject Recruitment and Informed Consent   
For Group B recruitment, consecutive potentially-eligible patients presenting to the study 
site will be offered the opportunity to participate in the study by the investigator. For both 
Groups A and B, subject recruitment will occur through the use of Sponsor and IRB-
approved advertisements and information sheets.  
 
The basic objective of the study, the potential benefits and risks of participating, use and 
protection of their personal information, and the option to not participate will be fully 
explained to all prospective subjects as specified in and in compliance with 21CFR§50, the 
Declaration of Helsinki, and according to the principles of ISO14155. The Investigator or 
delegated clinical site research staff will answer all questions to the subject’s satisfaction 
and will allow ample time for the subject to read the informed consent form and have 
additional questions answered. Subjects will be informed that the trial will be registered in 
the clinical trial registry databank maintained by the National Institutes of Health/National 
Library of Medicine (NIH/NLM).  All potential subjects will be informed through both 
verbal and written information, and will sign an informed consent, according to local 
requirements, which states that any withdrawal from the study will neither prejudice nor in 
any way affect their future treatment. Subject consent will be obtained in writing prior to 
any study-related subject data collection or procedures being performed on the subject. A 
copy of the completed informed consent form will be given to the subject and the original 
will be placed in the Investigator’s study record.  
 
If new information that may affect a subject’s willingness to participate or continue in the 
study, the Sponsor will notify the IRB and modify the informed consent form as 
appropriate.  
 
All individuals that sign the informed consent will be considered enrolled subjects. 
 
 
 
 
 
 


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12.4. 
Screening Evaluations 
After written informed consent is obtained, the subject is considered enrolled in the study 
and will be screened for inclusion and exclusion criteria.  
  
Screening evaluations may be conducted on day of procedure or at a separate visit up to 28 
days prior to procedure. The Screening Evaluations include (in any order): 
 
1. Medical history and concomitant/prior medications 
 
2. Cranial nerve physical exam 
 
3. Microscopic otoscopy with optional ear cleaning 
 
4. Tympanometry and Audiometry (in either order) 
 
5. Inclusion/Exclusion 
 
12.5. 
 Procedure 
12.5.1. Vital Signs (Group B) 
Vital signs (diastolic and systolic blood pressure, heart rate, respiratory rate and pulse 
oximetry) will be monitored 15 minutes and immediately prior to iontophoresis, and again 
immediately following iontophoresis, following tube placement, 30 minutes and 60 
minutes after completion of iontophoresis for all Group B subjects. 
 
12.5.2. Otoscopic Examination and Ear Preparation 
An otoscopic exam will be conducted using a microscope for all ears planned for treatment 
for subjects in Groups A and B prior to procedure.  The otoscopic examination will be used 
to visually examine the condition of the external ear canal and TM. Routine ear cleaning 
may be conducted, if needed, only to the extent necessary to ensure the tympanic membrane 
and ear canal are free from matter that may interfere with or influence the evaluation and 
to ensure visualization of the tympanic membrane. Changes in concomitant medications 
will be recorded. 
 
12.5.3. Earset Sizing 
The IPS Earset is available in 6 sizes. The ear sizing procedure will be performed according 
to the Instructions for Use (IFU) provided with the IPS. If the subject’s ear is not compatible 


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with the ear plug and fit cannot be established to ensure the earplug can properly seal in the 
ear canal, the subject will be considered a screening failure. 
 
12.5.4. Anesthetic Solution Preparation 
Ten (10) mL of 2% lidocaine/1:100,000 epinephrine anesthetic solution will be warmed to 
body temperature prior to instillation in the ear canal to minimize the caloric effect.  
 
12.5.5. Earset Placement and Drug Instillation 
Baseline tolerability will be assessed before placement of the Earset. The Earset ear plug 
of the size determined in the ear sizing procedure is then placed into the ear canal. Once 
the ear plug is positioned, the protective liner is removed, exposing the PSA to the ear canal. 
Circumferential pressure is applied through the ear plug against the surface of the ear canal, 
ensuring adhesion of the PSA. The Earset’s integrated fill system is used to instill the 
selected drug into the ear canal. This process is repeated for the second ear, as applicable.  
 
The Electrode Cable is snapped to the Return Electrode Patch. The Return Electrode Patch 
is then attached to the patient at a clean, dry site (such as the shoulder near the base of the 
neck) that is clear of lesions, bony protuberances and excessive hair. Prior to placing the 
return electrode on the patient, the investigator will assess the location for pre-existing 
erythema using the five point Draize erythema score where 0 indicates no erythema, 1 = 
very slight erythema (barely perceptible), 2 = well-defined erythema, 3= moderate to severe 
erythema, 4= severe erythema to slight eschar formation.43 The location will be assessed 
again following iontophoresis. 
 
12.5.6. Start of Iontophoresis 
To begin anesthesia, the applicable Control Unit button(s) are pressed to initiate current. 
Initiation of current represents the beginning of the iontophoresis procedure. There are two 
buttons, one for each ear. Without interruptions, the Control Unit operation will take 
approximately 10 minutes. Progress through the iontophoresis cycle can be monitored via 
the status bars on the Control Unit which fill to indicate progress toward completion.  
 
The procedure can be paused at any time, and then resumed. The Control Unit will account 
for these pauses to ensure consistent current dose delivery, and will provide a visible and 
audible signal when complete.  
 
For Group A subjects randomized to sham iontophoresis, all procedures will take place as 
described above.  The iontophoresis unit will not be activated, as dictated by the 
randomization schedule.  
 
 
 
 
 
 
 
 
 
 
 


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12.5.7. Anesthetic Solution and Return Electrode Patch Removal 
At the end of iontophoresis, the Earset(s), and Return Electrode Patch are removed and the 
anesthetic solution is removed from the ear canal either by wick or head tilting.  
 
The return electrode location will be assessed by the treating physician upon completion of 
iontophoresis and removal of the return electrode patch. Observations will be graded using 
the five point Draize erythema score where 0 indicates no erythema, 1 = very slight 
erythema (barely perceptible), 2 = well-defined erythema, 3= moderate to severe erythema, 
4= severe erythema to slight eschar formation.44 Scores of 3 or greater will be considered 
adverse events. 
 
12.5.8. Post-Iontophoresis Anesthesia Effectiveness (Group A) 
Following iontophoresis, the Investigator will inspect the ear canal and TM using the 
microscope. The Investigator will then lightly tap on the anterior half of the TM to elicit 
subject sensation (at the location where a tympanostomy tube would theoretically be 
placed) which is recorded via VAS.  
 
 
 
 
  
 
 
 
 
If an unexpected serious complication occurs during the procedure, the procedure will be 
terminated. The Investigator will take all appropriate intra- and post-treatment measures to 
ensure subject safety and proper treatment. The Investigator will notify Tusker Medical and 
their IRB immediately, but in no instances greater than 24 hours of the incident.  
 


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12.5.9. Post-Iontophoresis Anesthesia Effectiveness (Group B) 
Following iontophoresis, the Investigator will inspect the ear canal and TM using the 
microscope. The Investigator will then lightly tap on the anterior half of the TM at the 
location where the tympanostomy tube will be placed to elicit subject sensation which is 
recorded via VAS for each ear. 
 
 
 
The Investigator will assess whether the TM is adequately anesthetized for the 
tympanostomy tube placement based on subject response to the TM tap for each ear.  This 
tap assessment method has been used successfully in prior studies to determine adequate 
anesthesia for subsequent tympanostomy tube placement for both children and adults. 
 
12.5.10. Tympanostomy Tube Placement (Group B only) 
In at least one ear, the Investigator will place the TT using the TDS while the subject’s head 
is gently stabilized by the clinic staff, as is typical for standard of care ear examinations. If 
the TT is not successfully placed by the TDS device, the investigator may choose to attempt 
tube placement with another TDS device. 
 
 
 
 
 
  
 
Following TDS tube placement, the subject will report their post-tube placement ear 
discomfort for each ear undergoing tube placement using the VAS.  For bilateral tube 
placement subjects, the ‘worst’ ear pain score (highest score) will be used for analysis of 
the tube placement tolerability primary endpoint. 
 
 
 
 
 
 
 
 
  The subject’s VAS score for each ear following suction 
will be recorded. Post-operative care, including otic drops, will be prescribed per 
investigator’s discretion. All post-operative medications will be documented. 
 
If an unexpected serious complication occurs during the procedure, the procedure will be 
terminated. The Investigator will take all appropriate intra- and post-treatment measures to 
ensure subject safety and proper treatment. The Investigator will notify Tusker Medical and 
their IRB immediately, but in no instances greater than 24 hours of the incident.  
 
12.5.11. 
Cranial Nerve Exam 
The cranial nerve physical exam will be conducted post-procedure. 
 


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12.6. Group A Follow-up 
Follow-Up Visit at 3 Days Post-Procedure (-1/+2 Days) 
 
1. All subjects are required to return for the 3-day post-procedure follow-up visit. 
 
2. A microscopic otoscopic examination will be used to visually examine the condition of 
the external ear canal and TM. If any adverse otoscopic findings are observed, 
microscopic images will be collected for each ear. 
 
3. The subject will complete audiometry and tympanometry, and cranial nerve physical 
exam. 
 
4. The ears will be evaluated for any adverse events.  
 
5. If there are suspected procedure, device or drug-related adverse findings, the subject is 
required to return for follow-up at 12 ± 3 days post-procedure. 
 
6. If there are no unresolved suspected procedure, device or drug-related adverse findings, 
the subject will then be exited from the study. 
 
7. Follow-up for other adverse events will be determined according to Investigator 
discretion. 
 
Follow-Up Visit at 12 Days Post-Procedure (±3 Days) 
 
1. Only subjects with suspected procedure, device or drug-related adverse events that are 
not resolved at the 3-day visit, or per Investigator decision, are required to complete the 
12 days post-procedure follow-up visit. 
 
2. A microscopic otoscopic examination will be used to visually examine the condition of 
the external ear canal and TM. If any adverse otoscopic findings are observed, 
microscopic otoscopic images will be collected for each ear. 
 
3. The ears will be evaluated for any new or ongoing adverse events.  
 
4. The subject will complete audiometry and tympanometry, and cranial nerve physical 
exam. 
 
5. The subject will then be exited from the study. 
 
12.7. 
Group B Follow-up 
3-Week Post-Procedure Follow-Up Visit (+/- 7 Days) 
 
1. All subjects are required to return for the 3-week post-procedure follow-up visit. 
 
2. An otoscopic examination will be used to visually examine the condition of the external 
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which cannot be attributed to natural history or progression of the disease. This definition 
does not depend on the causal relationship with the device, drug or protocol requirements. 
 
Any change of clinical significance, including vertigo, nausea and vomiting, derived from 
the protocol evaluations including observations and patient-reported findings will be 
included as adverse events. Changes in vital signs 30% or greater compared to baseline will 
be considered adverse events. 
 
All Adverse Events (AEs) will be recorded on dedicated AE case report forms. The event, 
date of onset, severity, seriousness, duration, treatment, outcome, date or resolution and 
relationship to device, procedure or drug will be recorded on the AE case report form 
(CRF). AEs will be categorized by seriousness, relatedness to procedure, investigational 
drug, or device whether anticipated or unanticipated. All adverse events will be coded using 
standard terms.  
 
13.2. 
Serious Adverse Events 
If an unexpected serious complication resulting in an adverse event occurs during the 
procedure, the procedure will be terminated. The Investigator will take all appropriate intra- 
and post-procedural measures to ensure subject safety and proper treatment. In the event of 
a serious adverse event at any time during the study, the Investigator will notify the Sponsor 
and their IRB immediately or no later than within 24 hours. 
 
All Serious Adverse Events that have not resolved by the end of the subject's participation 
in the study must be followed until the event resolves, improves, or stabilizes. The 
investigator should report any follow-up information as it becomes available. 
 
13.3. 
Adverse Event Definitions  
Adverse Event (AE) 
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated 
with the procedure or use of the device or investigational drug, and does not imply judgment 
about causality.  
 
Serious Adverse Event (SAE) 
AEs are classified as serious or non-serious. A serious adverse event is any AE that is: 
 
• Fatal 
 
• Life-threatening 
 
• Requires or prolongs hospital stay 
 
• Results in persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 
• Led to fetal distress, fetal death or congenital abnormality or birth defect 
 


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• An important medical event that may jeopardize the subject, and may require medical 
or surgical intervention to prevent one of the other serious outcomes noted above.  
 
Life Threatening Adverse Event or Life-Threatening Suspected Adverse Reaction 
An adverse event or suspected adverse reaction is considered life threatening if, in the view 
of either the investigator or sponsor, its occurrence places the subject at immediate risk of 
death. It does not include an adverse event that, had it occurred in a more severe form, 
might have caused death. 
 
Unanticipated Adverse Device Effect (UADE) 
A UADE is any serious adverse effect on health or safety or any life-threatening problem 
or death caused by, or associated with, a device, if that effect, problem or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan 
or application, or any other unanticipated serious problem associated with a device that 
relates to the rights, safety, or welfare of subjects.  
 
In order to ensure subject safety during the study, all adverse events assessed as “serious” 
in the opinion of the Investigator will be reviewed by the Medical Monitor to determine 
any causal relationship to the study drug, device or procedure. All adverse events that do 
not meet any of the criteria for serious should be regarded as non-serious adverse events. 
Non-serious adverse events must still be documented on the appropriate CRF. 
 
Reporting 
The sponsor will notify FDA, all reviewing IRBs and all participating Investigators of 
potential serious risks, from this study or any other source, as soon as possible, but in no 
case later than 15 calendar days after the Sponsor determines that the information qualifies 
for reporting, including: 
 
1. Suspected adverse drug reactions that are considered both serious and unexpected, 
 
2. Findings from other studies that suggest a significant risk in humans exposed to the 
drug,  
 
3. Findings from animal or in vitro testing that suggest a significant risk in humans 
exposed to the drug, and  
 
4. An increased rate of occurrence of serious suspected adverse reactions. 
 
In addition, the sponsor will notify FDA, all reviewing IRBs and participating investigators 
within 10 working days after the Sponsor first receives notice of an Unanticipated Adverse 
Device Effect.  
 
13.4. 
Adverse Event Classification  
Adverse Event Severity  
All adverse events will be classified as to the severity of the event based on the definitions 
consistent with AE severity grading scale provided by the National Cancer Institute, of the 
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during preparation during procedure), nature of the malfunction and relatedness to potential 
adverse events will be collected on appropriate CRFs. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14.0 
 STATISTICAL METHODS  
This study will consist of two independent Groups, referred to as Group A and Group B.  
Each group has its own primary endpoint, each of which must pass the statistical test for 
the overall study to be considered successful. 
 
Group A will consist of 40 healthy adult subjects aged 18-50, enrolled at two 
investigational centers in the US. Group A subjects will be randomized to receive 
unilateral (1 ear) active lidocaine iontophoresis or unilateral sham lidocaine iontophoresis.  
The sham iontophoresis procedure will be identical to the active lidocaine iontophoresis, 
with the exception that the iontophoresis channel will not be activated (ie, the same drug 
solution will be applied to both ears).  After the completion of the iontophoresis, the 
tympanic membrane will be tapped with a dull otologic probe to test anesthesia 
effectiveness. The subject will rate the level of pain using the VAS after the ear is tapped.   
 
Group B will consist of 30 adults age 18 years or older who require unilateral or bilateral 
tube insertion, enrolled at up to 9 centers in the US.  Group B subjects will receive active 
lidocaine iontophoresis and tube insertion using the TDS in all ears that require tube 
insertion.  The subject will rate the pain on tube insertion using the VAS, and the pain 
score will be compared to a fixed performance goal.  
 
14.1. 
Subject Disposition  
The number and proportion of subjects in Groups A & B eligible for and compliant with 
all follow-up examinations will be presented. Subjects who withdraw from the study will 
be tabulated with the reasons for the withdrawal. Subjects who initiate the procedure, 
regardless of tolerability outcome or anesthesia effectiveness, will be encouraged to 
return for all follow-up assessments. 
 
14.2. 
General Statistical Methods 


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Descriptive statistics will be provided. Data collected in the study will be summarized 
overall and as defined in the protocol.  
 
Routine presentation of continuous variables in descriptive tables will include mean, 
standard deviation, sample size, and median. Categorical or binary variables will be 
presented with numerator, denominator, and percent.  
 
The SAS system (v9.2 or later) or R will be used to perform all statistical analyses. 
 
14.3. 
Group A – Statistical Methods 
14.3.1. Randomization & Blinding 
Subjects will be randomized (1:1) to either active lidocaine iontophoresis or sham 
lidocaine iontophoresis. Randomization will be stratified by site and will be balanced 
by using permuted blocks. 
 
 
  
 
The study will be double-blinded such that the Investigator and subjects will be blinded 
to treatment assignment to minimize bias regarding Investigator and Subject-reported 
outcomes. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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14.3.2. Analysis Sets 
14.3.2.1. Modified Intention to Treat (mITT) 
The mITT analysis set includes all subjects who are randomized and in whom the 
lidocaine is introduced into the ear canal. Subjects who discontinue iontophoresis 
prior to the TM tap assessment or decline TM tap assessment will provide a pain 
score for the attempted procedure and will be included in the mITT. Only subjects 
who do not complete the procedure due to reasons not related to iontophoresis 
discomfort (eg, anatomy not compatible with device fit) will be excluded. 
Subjects will be analyzed as randomized. 
 
14.3.2.2. Per Protocol Set 
The Per Protocol Set is a subset of the mITT and includes all mITT subjects 
without major protocol deviations. Major protocol deviations include: 
• Eligibility violations 
• Procedural deviations with the potential to affect anesthesia efficacy (eg, 
abbreviation of iontophoresis or use of incorrect local anesthesia drug). 
 
14.3.2.3. 
Safety Analysis Set 
The Safety Analysis Set will include all subjects in whom the lidocaine solution 
is introduced into the ear canal (same as the mITT set). 
 
14.3.3. Primary Endpoint Analysis 
Group A subjects are randomized to either active lidocaine iontophoresis or sham 
lidocaine iontophoresis. Each subject will have a VAS score.   
 
The null and alternative hypotheses are:  
 
Ho :  µT- µS= 0 
vs. 
H1 : µT- µS < 0 
 
where µT and µS are the mean scores in the treatment and sham arms respectively. 
 


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The primary endpoint will be evaluated in the mITT set using a permutation test at a 
2.5% significance level. The primary endpoint will be demonstrated if the p-value from 
the permutation test is less than or equal to 0.025.   
 
14.3.4. Safety Analysis 
All reported or observed adverse events that occur for subjects in the Safety Analysis 
Set during or after the procedure will be recorded. All AEs will be tabulated by 
treatment group. AEs will be summarized by preferred terms and system organ class 
using the Medical Dictionary for Regulatory Activities (MedRA). The frequency of 
each event will be summarized by seriousness, severity and by relationship to the study 
device, procedure and/or drug. Separate summaries will be provided for SAEs and AEs 
related to study device, procedure and/or drug. In the event a subject reports the same 
event several times (eg, otalgia), the first occurrence of the worst reported case of the 
event will be used for the purpose of analysis.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
14.4. Group B – Statistical Methods 
14.4.1. Analysis Sets 
14.4.1.1. Full Analysis Set (FAS) 
The FAS includes all subjects in whom the lidocaine solution is introduced into the 
ear canal.  
 
14.4.1.2. Per Protocol Set 


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The Per Protocol Set is a subset of the FAS and includes FAS subjects without major 
protocol deviations. Major protocol deviations include: 
• Eligibility violations 
• Procedural deviations with the potential to affect anesthesia efficacy (eg, 
abbreviation of iontophoresis or use of incorrect local anesthesia drug). 
 
14.4.1.3. Safety Analysis Set 
The Safety Analysis Set will include all subjects in whom the lidocaine solution is 
introduced into the ear canal (same as FAS). 
 
14.4.2. Primary Endpoint Analysis 
Group B subjects will each have a VAS score that captures the pain associated with 
tube insertion. 
 
The null and alternative hypotheses are: 
 
H0: µ ≥ 4.5 
H1: µ < 4.5 
 
where µ is the mean VAS score across subjects. 
 
The primary endpoint will be evaluated in the Per Protocol set using the bootstrap 
method at a 2.5% significance level. The primary endpoint will be demonstrated if the 
upper confidence bound of a 95% non-parametric bootstrap confidence interval on the 
mean score is below 4.5.  For bilateral subjects the highest score (‘worst ear’) will be 
used as the subject score. If a subject is intended for unilateral treatment, then the score 
from only the treated ear is collected and included in the analysis. The primary analysis 
for Group B will be performed based on completers in the Per Protocol set, specifically 
including only subjects with VAS scores following successful tube insertion for all ears 
indicated for treatment (both ears for bilateral subjects and one ear for unilateral 
subjects). 
 
 
 
  
 
14.4.3. Safety Analysis 
All reported or observed adverse events that occur for subjects in the Safety Analysis 
Set during or after the procedure will be recorded. All AEs will be tabulated. AEs will 
be summarized by preferred terms and system organ class using the Medical Dictionary 
for Regulatory Activities (MedRA). The frequency of each event will be summarized 
by seriousness, severity and by relationship to the study device, procedure and/or drug. 
Separate summaries will be provided for SAEs and AEs related to study device, 
procedure and/or drug. In the event a subject reports the same event several times (eg, 
otalgia), the first occurrence of the worst reported case of the event will be used for the 
purpose of analysis.  
 


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14.6. 
Handling Drop Outs or Missing Data 
Group A Primary Endpoint: If a subject in Group A discontinues iontophoresis prior to 
the TM tap assessment or declines TM tap assessments, the subject will provide a VAS 
pain score for the attempted procedure and will be included in the analysis of the 
primary endpoint. 
 
 
 
 Reasons for discontinuation will be 
documented and presented in the clinical study report.   
 
Group B Primary Endpoint: If a subject in Group B discontinues iontophoresis or tube 
placement, the subject will provide a VAS pain score for the attempted procedure. 
Subjects with discontinued procedures will be included in the sensitivity analyses only, 
and will not be included in the primary analysis. Only subjects with scores after tubes 
are successfully placed in all indicated ears (one tube if indicated for unilateral 
treatment and two tubes if indicated for bilateral treatment) will be included in the 
primary analysis.  
 
 
 
 
 
 
 Reasons for discontinuation will be documented and presented in 
the clinical study report. 
 
 
 
 
 
 
 
14.7. 
Multiplicity Adjustment 
Groups A & B each have a single primary endpoint tested at a significance level of 
2.5%.  Each primary endpoint must pass the statistical test for the study to be considered 
successful.  The familywise error rate is therefore controlled at 2.5% and no multiplicity 
adjustments are planned. 


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15.0 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
Prior to enrolling subjects, all sites must have the approval of an Institutional Review Board 
(IRB) responsible for reviewing clinical studies at the study site. The IRB must also 
approve the subject Informed Consent as well as recruiting advertisements and subject-
facing information. Amendments to any of these documents must also be approved by the 
IRB. No subjects will be consented or enrolled to a site until IRB approval has been 
received in writing. The Informed Consent process is described in Section 12.3.  
 
15.1. 
Subject Confidentiality 
Subject confidentiality will be maintained at all times during the study. A unique subject 
identifier will consist of (1) a Protocol Identifier, (2) an Investigational Site identifier, and 
(3) a consecutive subject number with designated group assignment (A or B).  
 
Example: 7003-JON-A01 in Group A 
 
7003 = 4 digit Protocol Number 
 
JON = Investigator Dr. Jones 
 
A01 = Number of subject enrolled 
 
The Investigator or evaluation personnel at each study site will assign the subject identifier 
and access to this identifier will be restricted to the Investigator and evaluation personnel. 
The key to the subject identifier and subject data collection sheets containing the subject’s 
name and identification code will be securely maintained at each study site. 
 
 
16.0 
PREMATURE TERMINATION OR WITHDRAWAL 
16.1. 
Subject Stopping Criteria 
Subjects who do not complete the study procedure will be encouraged to remain in the 
study to complete post-procedure evaluations. If a subject withdraws prematurely from the 
study, a genuine effort must be made to determine the reason(s) why the subject failed to 
return for the procedure or follow-up visit or discontinued the study, and the reason must 
be recorded on the appropriate CRF. 
 
Potential reasons for discontinuation include: 
 
• Subject decides it is in their best interest to withdraw 
 
• Subject expresses intolerable discomfort during the procedure and indicates they 
wish to stop the procedure and withdraw 


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• Serious adverse event that requires withdrawal from the study 
 
• Investigator decides it is in the subject’s best interest to be withdrawn if subject is 
experiencing intolerance or intolerable reaction to the procedure.  
 
If the subject wishes to discontinue participation in the study, the Investigator will attempt 
to have the subject continue participation to complete follow-up assessments unless the 
subject’s safety is compromised.  All Serious Adverse Events that have not resolved by the 
end of the subject's participation in the study, must be followed until the event resolves, 
stabilizes or becomes non-serious.  
 
All potential subjects in the study will be verbally informed and will sign an informed 
consent in compliance with 21CFR §50 that states that any withdrawal from the study will 
neither prejudice nor in any way affect their future treatment. 
 
Prior to designating a subject as lost to follow-up, the site must provide documented 
evidence of three (3) good faith attempts to contact the subject to which there has been no 
response. At that point the subject will be considered lost-to-follow-up and withdrawn from 
the study. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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17.0 
INVESTIGATOR RESPONSIBILITIES 
Investigators who participate in this study will conduct the study according to the protocol, 
the Declaration of Helsinki, GCP and applicable regulatory requirements. Tusker Medical 
will sponsor the conduct of the study at up to 8 investigational centers. This study will be 
performed under the direction and responsibility of the physician investigator at each study 
site. It is the responsibility of the Investigators to ensure study material is reviewed and 
approved by all applicable Institutional Review Boards (IRB), hospital committees, and 
administrative personnel as required.  
 
The Investigator is responsible for the execution of the study, proper performance of 
participating personnel, ensuring adherence to the protocol and schedule of procedures, and 
for the control of devices under investigation. The Investigator is also responsible for 
protecting the rights, safety, and welfare of subjects under the investigator's care, and 
ensuring that written informed consent is obtained.  
 
The Investigator is responsible for data confidentiality, quality, and completeness, and 
proper data storage in a secure file for a period of time as indicated in the protocol, Clinical 
Trial Agreement (CTA) and if mandated, by the respective IRBs. 
 
The Investigator and site personnel directly involved with the study will receive training in 
the protocol and use of devices prior to initiation of the study. This training will be 
conducted by the Sponsor (Tusker Medical, Inc.) or designee, prior to initiation of the 
study.  
 
18.0 
SPONSOR 


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Tusker Medical, Inc. is the device manufacturer as well as the study sponsor (“Sponsor”). 
The Sponsor will work with the study site under the terms of the Clinical Trial Agreement 
(CTA).  
 
The Sponsor contact is as follows: 
 
Tusker Medical, Inc. 
155 Jefferson Drive, Suite 200 
Menlo Park, CA 94025 
 
 
 
 
  
 
 
19.0 
 MONITORING 
Tusker Medical, Inc. (Sponsor) or designee will monitor the study sites to ensure 
investigators are in compliance with the protocol; subject informed consent forms are 
properly completed; adequate protection of the rights of the human subjects and the quality 
and integrity of the resulting data; study data is verified against source documents for key 
safety and effectiveness variables; investigational devices and drug are properly controlled; 
and verification that reports are filed in accordance with the protocol and the appropriate 
regulations. Monitoring will be conducted according to the Sponsor’s monitoring 
procedure and study monitoring plan. 
 
20.0 
INVESTIGATIONAL PRODUCT ACCOUNTABILITY 
Access to investigational drug and devices shall be controlled and the investigational drug 
and devices shall be used only in the clinical investigation and according to the protocol. 
The Sponsor shall keep records to document the physical location of all investigational 
drug and devices from shipment to the investigation sites until return or disposal. Drug and 
devices will be stored according to product labeling. The principal investigator or an 
authorized designee shall keep records documenting the receipt, use, return, and disposal 
of the investigational drug and devices, which shall include (a) the date of receipt, (b) 
identification of each investigational drug and device (batch number/serial number or 
unique code), (c) the expiration date, (d) the date or dates of use, (e) subject identification, 
and (f) the date of return of unused, expired or malfunctioning investigational products, if 
applicable. 
 
21.0 
DEVIATIONS 
A protocol deviation is defined as any event where the Investigator or site personnel deviate 
from the study protocol or study procedures for any reason. It is the Investigator’s 
responsibility to ensure that there are no protocol deviations throughout the life of the study. 
In the event that a non-emergency protocol deviation is identified, at the time of 
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corrective actions to prevent recurrence. The IRB will be notified as applicable. Any 
deviations from this protocol will be documented by the site on a protocol deviation CRF.  
 
 
 
22.0 
 DATA HANDLING AND RECORD KEEPING  
22.1. Source Data and Case Report Forms 
 
All study data will be captured on source documents by the Investigational Site. Data 
from the source documents will be recorded to CRFs by site personnel that have been 
trained on the protocol and CRF completion.  
 
22.2. Data Quality Assurance 
Accuracy and reliability of the clinical study data will be ensured by selection of 
qualified investigators, and appropriate study centers, review of protocol procedures 
with the investigators and associated personnel prior to the study, and by periodic 
monitoring visits by the sponsor. CRFs will be reviewed for accuracy and completeness 
by the sponsor during on site monitoring visits and after their return to the sponsor, and 
any discrepancies will be resolved with the investigator or designees, as appropriate.  
 
22.3. Record Retention 
All clinical sites will maintain all records pertaining to this study for a minimum of two 
years after marketing approval or formal discontinuation of investigational product 
development. The Sponsor will notify the clinical sites of the date of discontinuation. 
No study-related records, written or electronic, will be destroyed or transferred without 
specific written approval by the Sponsor.  
 
23.0 
 PUBLICATION POLICY 
The CTA mutually signed by the Investigator(s) and Tusker Medical, Inc., defines and 
describes the nature of the study agreement. 
 
The Sponsor retains the rights to this protocol and the CRFs before and after data entry. 
Tusker Medical, Inc. reserves the right to review any reports of this study to verify that the 
information is accurate and to ensure the content and timing of any such publication is 
mutually agreed upon by the Investigator(s) and Tusker Medical, Inc. Draft abstracts, 
manuscripts, and materials for presentation at scientific meetings should be provided to the 
sponsor at least 30 working days prior to submission. 
 
Clinical trial information will be registered in the clinical trial registry databank maintained 
by the National Institutes of Health/National Library of Medicine (NIH/NLM) per FDAAA 
801 requirements. If a future publication results from this study, authorship will be 
established according to ICMJE guidelines.  
 
 
 


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24.0  REFERENCES  
1 Rosenfeld RM, Schwartz SR, Pynnonen MA, Tunkel DE, Hussey HM, Fichera JS, Grimes 
AM et al. Clinical practice guideline: tympanostomy tubes in children. Otolaryngol Head 
Neck Surg, 2013; 149(IS):S1-S35. 
2 AAO-HNS Clinical Indicators, 2010: 
https://www.societyformiddleeardisease.org/Content/ClinicalIndicators/Myringotomy-and-
Tympanostomy-Tubes-CI.pdf. Accessed on 02 July 2016. 
3 Otitis Media (Ear Infection), NIDCD, July 2002. NIH Pub No. 97-4216. 7 Aug 2008 
http://www.nidcd.nih.gov/health/hearing/ otitism.asp. 
4 Klein J, Pelton S. Epidemiology, pathogenesis, clinical manifestations, and complications of 
acute otitis media. Up to Date, October 2008, 7 Aug 2008. 
5 Tusker Medical analysis of Truven Commercial, Medicaid and Medicare databases. 
6 Litman RS. Basics of Pediatric Anesthesia. Philadelphia, PA, 2013. 
7 Dewhirst E, Fedel G, Raman V et al. Pain management following myringotomy and tube 
placement: Intranasal dexmedetomidine versus intranasal fentanyl. Int J Pediatr 
Otorhinolaryngol, 2014; 78(7):1090-1094. 
8 Montague ML, Lee MSW, Hussain SSM. Human error identification: an analysis of 
myringotomy and ventilation tube insertion. Arch Otolaryngol Head Neck Surg, 
2004;130:1153-1157. 
9 Isaacson G. Six sigma tympanostomy tube insertion: achieving the highest safety levels 
during residency training. Otolaryngol Head Neck Surgery, 2008; 139:353-357. 
10 Kesser BW, Derebery MJ, Friedman RA. (2010) Surgery of ventilation and mucosal 
disease. In: Otologic Surgery. Brackmann DE, ed. Pages 73- 91 (Philadelphia, PA: Saunders, 
2010). 
11 Freeman SRM, Iseli CE, Kerr MBA, Kong JHK, Gibson WPR. Phenol application for 
tympanic membrane anesthesia. Clin Otolaryngol, 2007; 33:152-199. 
12 EMLA drug label; 
http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=1240, accessed 
03June2016. 
13 Jyvakorpi M. A comparison of topical EMLA cream with Bonain’s solution for anesthesia 
of the tympanic membrane during tympanocentesis. Eur Arch Otorhinolaryngol, 1996; 253: 
234-236. 
14 Todd N. What your colleagues think of tympanostomy tubes 28 years later. Laryngoscope, 
1999; 109:1028-1032. 
15 Markowitz-Spence L, Brodsky L, Syed N, Stanievich J, Vold M. Anesthetic complications 
of tympanostomy tube placement in children. Arch Otolaryngol Head Neck Surg, 2006; 116: 
809-812. 
16 Hoffmann KK, Thompson GK, Burke BL, Derkay CS. Anesthetic complications of 
tympanostomy tube placement in children. Arch Otolaryngol Head Neck Surg, 2002; 128: 
1040-1043. 
17 Ing C, Dimaggio C, Whitehouse A et al. Long-term differences in language and cognitive 
function after childhood exposure to anesthesia. Pediatrics, 2012; 130: e476. 
18 Wilder RT, Flick RP, Sprung J et al. Early exposure to anesthesia and learning disabilities 
in a population- based birth cohort. Anesthesiology, 2009; 110: 796. 
                                                 




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39 Jensen MP, Chen C, Brugger AM. Interpretation of visual analog scale ratings and change 
scores: a reanalysis of two clinical trials of postoperative pain. J Pain, 2003; 4(7):407-414. 
40 Rosenfeld RM, Schwartz SR, Pynnonen MA, Tunkel DE, Hussey HM, Fichera JS, Grimes 
AM et al. Clinical practice guideline: tympanostomy tubes in children. Otolaryngol Head 
Neck Surg, 2013; 149(IS):S1-S35. 
41 AAO-HNS Clinical Indicators, 2010: 
https://www.societyformiddleeardisease.org/Content/ClinicalIndicators/Myringotomy-and-
Tympanostomy-Tubes-CI.pdf. Accessed on 02 July 2016. 
42 http:www.amda.com/tools/library/whitepapers/hopsiceinltc/appendix-a.pdf. Accessed on 09 
Feb 2017. 
43 Draize JH, Woodard G, Calvery HO. Methods for the study of irritation and toxicity of 
substances applied topically to the skin and mucous membranes. J. Pharmacol. Exp. 
Therapeutics, 1944; 82: 377–390. 
44 Draize JH, Woodard G, Calvery HO. Methods for the study of irritation and toxicity of 
substances applied topically to the skin and mucous membranes. J. Pharmacol. Exp. 
Therapeutics, 1944; 82: 377–390. 
45 US Department of Health and Human Services, NIH, National Cancer Institute, “Common 
Terminology Criteria for Adverse Events (CTCAE), NIH Publication No 09-5410, Version 
4.03, June 14, 2010. 
46  The use of the WHO–UMC system for standardized case causality assessment. Accessed 
from: http://WHO-UMC.org/graphics/24734.pdf. accessed on 29 May 2016. 
47 Clark JG: Uses and abuses of hearing loss classification. ASHA, 1981; 23(7):493– 500. 
48 American Academy of Audiology Childhood Hearing Screening Guidelines, Sept 2011. 
Accessed from: http://www.cdc.gov/ncbddd/hearingloss/documents/AAA_Childhood 
%20Hearing%20Guidelines_2011.pdf. accessed on 29 May 2016. 
 
 
 

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
A PROSPECTIVE, MULTICENTER STUDY TO EVALUATE EFFECTIVENESS AND 
SAFETY OF LIDOCAINE IONTOPHORESIS AND TYMPANOSTOMY TUBE 
PLACEMENT USING THE TULA IONTOPHORESIS AND TUBE DELIVERY 
SYSTEMS FOR ADULTS IN AN OFFICE SETTING (ADEPT; ADult study to Evaluate 
Placement of tympanostomy Tubes in-office) 
Document Number: CPR007005, Revision E        Effective Date: 06/26/2017 
Protocol Number: CPR007003 Rev C 
Approvers 
Signature:  _________________________ 
Date:  
 _________________________ 
Signature:  _________________________ 
Date:  
 _________________________ 
Signature:  _________________________ 
Date:  
 _________________________ 
CONFIDENTIALITY STATEMENT 
Information contained in this document is confidential and proprietary to Tusker Medical. Except as 
otherwise agreed to in writing, by accepting or reviewing this document, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) 
or use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, 
Tusker Medical must be promptly notified.
NCT03119181


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TABLE OF CONTENTS 
 
1.0 
Scope .................................................................................................................... 4 
2.0 
Trial Objectives .................................................................................................... 4 
3.0 
Trial Endpoints..................................................................................................... 4 
3.1 
Co-Primary Endpoints ......................................................................................... 4 
3.2 
Safety Endpoint .................................................................................................... 4 
3.3 
Secondary Endpoints ........................................................................................... 4 
 
 .......................................................................................... 4 
4.0 
Trial Design ......................................................................................................... 5 
5.0 
Study Cohorts....................................................................................................... 6 
6.0 
Randomization and Blinding (Group A only) ..................................................... 6 
7.0 
Analysis Sets – Group A ...................................................................................... 7 
7.1 
Group A ............................................................................................................... 7 
7.1.1 Modified Intention to Treat (mITT) ..................................................................... 7 
7.1.2 Per Protocol .......................................................................................................... 8 
7.1.3 Safety Analysis Set .............................................................................................. 8 
7.2 
Group B ................................................................................................................ 8 
7.2.1 Full Analysis Set (FAS) ....................................................................................... 8 
7.2.2 Per Protocol Set.................................................................................................... 8 
7.2.3 Safety Analysis Set .............................................................................................. 8 
8.0 
Subject Disposition .............................................................................................. 8 
9.0 
Demographic Characteristics and Medical History ............................................. 9 
10.0 
Procedure Characteristics and Device Malfunctions ........................................... 9 
11.0 
Co-Primary Endpoint Analyses ........................................................................... 9 
11.1 
Anesthesia Effectiveness (Group A) .................................................................... 9 
11.2 
Tube Placement Tolerability (Group B) .............................................................. 9 
12.0 
Secondary Endpoint Analyses ........................................................................... 10 
13.0 
Sample Size and Power for Primary Endpoints ................................................. 10 
13.1 
Group A Primary Endpoint – Anesthesia Effectiveness .................................... 10 
13.2 
Group B Primary Endpoint – Tube Placement Tolerability .............................. 11 
14.0 
Safety Endpoint Analyses .................................................................................. 11 
14.1 
Adverse Events .................................................................................................. 11 
14.2 
Vital Signs .......................................................................................................... 12 
14.3 
Erythema Assessment at Return Electrode Location ......................................... 12 
14.4 
Audiometric Assessments .................................................................................. 13 
14.5 
Tympanometry ................................................................................................... 13 
14.6 
Otoscopic Assessments ...................................................................................... 13 
14.7 
Cranial Nerve Function ...................................................................................... 14 
15.0 
Prior and Concomitant Medications .................................................................. 14 
 
 ................................................................ 14 
17.0 
Handling of Missing Data .................................................................................. 14 
 
 ........................................................................................... 15 
 
 ........................................ 15 
 
 .......................................................................................... 15 
 
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 ...................................................................................... 16 
 
 .......................................................................... 16 
 
....................................................................................................... 17 
 
 .......................................................................................................... 17 
21.0 
Multiplicity Adjustment ..................................................................................... 17 
22.0 
Data Listings ...................................................................................................... 17 
23.0 
Definition of Variables ...................................................................................... 18 
23.1 
Baseline .............................................................................................................. 18 
23.2 
Study Day Calculation ....................................................................................... 18 
24.0 
Other General Considerations ............................................................................ 18 
25.0 
References .......................................................................................................... 18 
26.0 
Appendix - Code ................................................................................................ 18 
 
 
 
 




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4.0 
Trial Design 
This study is a prospective, multicenter evaluation of safety and effectiveness of 
iontophoresis and tympanostomy tube placement using the IPS and TDS for TT 
placement for adults in an office setting. 
 
The study will consist of two independent Groups. Each group has their own primary 
endpoint, each of which must pass the statistical test for the overall study to be 
considered successful:  
 
• 
Group A will consist of 40 evaluable healthy adult subjects aged 18-50 
(inclusive), enrolled at two investigational centers in the US.  Group A subjects 
will be randomized (1:1) to receive unilateral (1 ear) treatment with either active 
lidocaine iontophoresis or sham lidocaine iontophoresis.  The sham 
iontophoresis procedure will be identical to the active lidocaine iontophoresis, 
with the exception that the iontophoresis channel will not be activated (ie, the 
same drug solution will be applied to ears in both arms).  After the completion 
of the iontophoresis, the tympanic membrane will be tapped with a dull otologic 


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probe to test the level of anesthesia.   The subject will rate the level of pain 
using the VAS, and pain scores from the active iontophoresis group will be 
compared to the sham iontophoresis group.   
 
• 
Group B will consist of 30 evaluable adults age 18 years or greater who require 
unilateral or bilateral tube insertion enrolled at up to 9 centers in the US.  
Group B subjects will receive active lidocaine iontophoresis and will have 
tubes placed using the TDS in all ears indicated for tube placement.  The 
subject will rate the pain upon TDS tube insertion using the VAS, and the pain 
score (by subject) is compared to a fixed performance goal.  
 
5.0 
Study Cohorts 
There are two cohorts in the study: 
Group A: Healthy adult volunteers randomized to active lidocaine iontophoresis or 
sham lidocaine iontophoresis, followed by assessment of anesthesia effectiveness. 
Group B: Adults indicated for tympanostomy tube placement undergoing lidocaine 
iontophoresis and TDS-mediated tympanostomy tube placement, followed by 
assessment of tube placement tolerability. 
 
6.0 
Randomization and Blinding (Group A only) 
Subjects will be randomized (1:1) to either active lidocaine iontophoresis or sham 
iontophoresis. Randomization will be stratified by site and will be balanced by using 
permuted blocks. 
 
 
 
 
The study will be double-blinded such that the Investigator and subjects will be blinded 
to treatment assignment to minimize bias regarding Investigator and Subject-reported 
outcomes. 
 
 
 
 
 
 
 
  
 
 
 
 
 


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7.0 
Analysis Sets – Group A 
 
7.1 Group A 
 
7.1.1 Modified Intention to Treat (mITT) 
The mITT analysis set includes all subjects who are randomized and in whom 
the lidocaine is introduced into the ear canal. Subjects who discontinue 
iontophoresis prior to the TM tap assessment or decline TM tap assessment will 
provide a pain score for the attempted procedure and will be included in the 
mITT. 
 
 
 
   


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7.1.2 Per Protocol 
The Per Protocol Set is a subset of the mITT and includes all mITT subjects 
without major protocol deviations. Major protocol deviations include: 
 
• Eligibility violations 
• Procedural deviations with the potential to affect anesthesia efficacy (eg, 
abbreviation of iontophoresis or use of incorrect local anesthesia drug). 
 
7.1.3 Safety Analysis Set 
The Safety Analysis Set will include all subjects in whom the lidocaine solution 
is introduced into the ear canal (same as mITT set). 
 
7.2 Group B 
 
7.2.1 Full Analysis Set (FAS) 
 
The FAS includes all subjects in whom the lidocaine solution is introduced into 
the ear canal.  
 
7.2.2 Per Protocol Set 
The Per Protocol Set is a subset of the FAS and includes FAS subjects without 
major protocol deviations. Major protocol deviations include: 
• Eligibility violations 
• Procedural deviations with the potential to affect anesthesia efficacy (eg, 
abbreviation of iontophoresis or use of incorrect local anesthesia drug). 
 
7.2.3 Safety Analysis Set 
The Safety Analysis Set will include all subjects in whom the lidocaine solution 
is introduced into the ear canal (same as FAS). 
 
 
8.0 
 Subject Disposition 
The number and proportion of subjects in Groups A & B eligible for and compliant 
with all follow-up examinations will be presented. Subjects who withdraw from the 
study will be tabulated with the reasons for the withdrawal. Subjects who initiate the 
procedure, regardless of tolerability outcome or anesthesia effectiveness, will be 
encouraged to return for all follow-up assessments. 
 
Subject disposition will be summarized for each Group with counts and percentages. 
Categories summarized will include the number of subjects who signed informed 
consent, number of screen failures (with reasons), and the number enrolled, completed, 
and discontinued, as well as reasons for discontinuation. The summary of disposition 


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will also include the number and percentage of subjects included in each analysis set 
described in Section 7. 
 
9.0 
 Demographic Characteristics and Medical History 
Demographic characteristics including age, sex and race/ethnicity will be descriptively 
summarized for all enrolled subjects in each of the defined study Groups. Significant 
medical history will also be summarized for all enrolled subjects in each of the defined 
study Groups. Demographic characteristics and medical history will be presented 
separately for each of the Analysis Sets defined for each Group, and by sex. 
 
10.0 Procedure Characteristics and Device Malfunctions 
Procedure and device performance characteristics will be summarized using descriptive 
statistics for each Group, and by treatment for Group A only. 
11.0 Co-Primary Endpoint Analyses 
11.1  Anesthesia Effectiveness (Group A) 
This study will consist of two independent Groups, Group A and Group B.  Each Group 
has its own primary endpoint, each of which must pass the statistical test for the overall 
study to be considered successful.   
 
Group A subjects will be randomized to either active lidocaine iontophoresis treatment 
or sham lidocaine iontophoresis treatment. Each subject will each have a VAS score.    
 
The null and alternative hypotheses are:  
 
Ho :  µT- µS= 0 
vs. 
H1 : µT- µS < 0 
 
where µT and µS are the mean scores in the treatment and sham arms respectively. 
 
The primary endpoint will be evaluated in the mITT set using a permutation test at a 
2.5% significance level. The primary endpoint will be demonstrated if the p-value from 
the permutation test is less than or equal to 0.025.  These analyses will be repeated in the 
Per Protocol Set. 
 
 
11.2  Tube Placement Tolerability (Group B) 
The Group B primary endpoint is Tube Placement Tolerability defined as mean 
subject-reported pain score following TDS tube placement using the VAS. The mean 
pain score for subjects in the Group B cohort, for whom tube placement was 
attempted, will be evaluated against a Performance Goal pain score of 4.5.  
 


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Group B subjects will each have a VAS score that captures the pain associated with 
tube insertion. 
 
The null and alternative hypotheses are: 
 
H0: µ ≥ 4.5 
H1: µ < 4.5 
 
where µ is the mean VAS score across subjects. 
 
The primary endpoint will be evaluated in the Per Protocol set using the bootstrap 
method at a 2.5% significance level. The primary endpoint will be demonstrated if the 
upper confidence bound of a 95% non-parametric bootstrap confidence interval on 
the mean score is below 4.5.  For bilateral subjects the highest score (‘worst ear’) will 
be used as the subject score. If a subject is intended for unilateral treatment, then the 
score from only the treated ear is collected and included in the analysis. Only 
completers, i.e., subjects with VAS scores after successful tube insertion in all 
indicated ears will be included in the primary analysis. 
 
 
12.0  Secondary Endpoint Analyses 
There are no secondary endpoints for the study. 
 
13.0 Sample Size and Power for Primary Endpoints 
 
13.1 
Group A Primary Endpoint – Anesthesia Effectiveness 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
                                                 
 
 


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Twenty-four evaluable subjects in Group A will provide >95% power to detect the 
assumed mean difference in mean pain scores between Sham and Treatment. In order to 
account for uncertainty about the effect size, a total sample size of 40 is planned. 
Assuming 10% attrition (screen failure or withdrawn) in Group A, a sample size of 44 
subjects is expected to yield an evaluable sample size of 40.   
 
13.2 
Group B Primary Endpoint – Tube Placement Tolerability  
 
 
 
 
 
 
 
 
 
 
 
 
A sample size of 30 evaluable subjects in Group B will provide greater than 95% 
power at the one-sided 2.5% significance level for a non-parametric bootstrap test of 
the mean VAS score against a performance goal of 4.5.  
 
 
14.0 Safety Endpoint Analyses 
14.1 
Adverse Events 
Adverse events (AEs) reported during the study will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). The number and percentage of 
subjects reporting adverse events will be summarized by MedDRA system organ class 
and preferred term for each Group (A and B).  
 
The frequency of each event will be summarized by seriousness, severity and by 
relationship to the study device, procedure and/or drug. For all AE tables, a subject 
reporting the same AE more than once will be counted once when calculating the 
number and percentage of subjects with that particular event. If a subject reports the 
same AE more than once or has the same AE on multiple occasions, the maximum 
severity grade recorded for the event will be presented. 
 
Overall summaries of serious and non-serious AEs will be presented.  The overall 
summaries will include the number and percentage of patients experiencing AEs 
classified by treatment, relationship to device/procedure/study drug, MedDRA SOC 
(System Organ Class) and preferred term. Summaries of AEs will also be presented by 
severity for each treatment group including the number and percentage of patients 


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experiencing AEs classified by relationship to device/procedure/study drug, SOC and 
preferred term. 
Safety events will be reported for all subjects in which the lidocaine solution was 
introduced into the ear (Safety Analysis Set) and will be reported for the following time 
intervals:  
• Events occurring during the procedure visit  
• Events occurring between the procedure through the subject’s final follow-up 
visit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
Complete patient listings of all AEs will be provided.  For each AE the following will 
be specified: start and stop dates, severity grade and MedDRA SOC, relationship to 
study device, relationship to procedure, relationship to study drug, action taken, 
outcome of the adverse event and seriousness, where appropriate.  Any unanticipated 
adverse events will be noted. 
14.2 
Vital Signs 
Descriptive statistics of mean, SD, minimum, and maximum will be presented for vital 
signs measurements (systolic blood pressure, diastolic blood pressure, heart rate, 
respiratory rate, blood oxygen saturation) at all protocol-defined time points.  Mean and 
median change from baseline to post-iontophoresis time point for each vital sign will be 
presented for the three protocol-defined post-iontophoresis time points (0, 30 and 60 
minutes post) by treatment group.   Any clinically significant change in vital sign 
measurements (30% or greater change from baseline) will be reported as an adverse 
event. 
 
14.3 
Erythema Assessment at Return Electrode Location 
Erythema observed for the skin under the return electrode will be assessed by the 
treating physician and categorized by grade level (0 through 4) prior to and 
immediately after iontophoresis.  Erythema findings will be summarized by number 


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and proportion of subjects in the Safety Analysis Set for each erythema grade level for 
each Group. Number and proportion of subjects reporting discomfort at the return 
electrode location will be summarized. 
14.4 
Audiometric Assessments 
Change in audiometric measurements (shifts) from baseline to each follow-up visit for 
subjects in the Safety Analysis Set will be presented using descriptive statistics (mean, 
SD, median, minimum and maximum). Shifts in air conduction (AC) and bone 
conduction (BC) hearing thresholds will be reported for each frequency (500, 1000, 
2000 and 4000 Hz) on a by-ear basis, and for each treatment arm in Group A (active or 
sham treatment). Shifts from baseline to each follow-up visit in air-bone gap (air 
conduction minus bone conduction) will also be reported for each frequency (500, 
1000, 2000 and 4000 Hz) on a by-ear basis, and for each treatment arm in Group A. 
Shifts in air conduction pure tone average (AC PTA), bone conduction PTA (BCA) and 
air-bone gap averages will be presented for each follow-up time point by ear for each 
Group and by treatment.  For all PTA measurements, the PTA will be calculated by 
adding the threshold levels in decibels (dB) obtained at each frequency tested divided 
by number of frequencies tested.   
Shift tables for air conduction pure tone averages greater than 15 dB (>15dB) by ear 
will be calculated, and presented by ear for each Group and by treatment for each 
follow-up time point. 
 
Degree of hearing loss severity will be defined according to the protocol (slight through 
profound) and presented by subject for each Group and by relationship to study device, 
procedure or study drug. 
 
14.5 
Tympanometry 
Tympanometry results are used to assess of tube patency (for Group B only) and for 
changes in middle ear condition. Tympanometry will be performed for both ears for all 
subjects (Groups A and B) at screening and at all follow-up visits.  The number and 
percentage of ears in each Group with tympanogram types A, B or C will be presented 
for all subjects and for each treatment arm (sham or active treatment in Group A) in the 
Safety Analysis Set at screening and all follow-up time points.  
14.6 
Otoscopic Assessments 
Otoscopic examination will be performed in all ears intended for treatment at all 
protocol-defined time points.  The number and percentage of ears in each Group with 
abnormal findings for the external acoustic meatus or tympanic membrane will be 
presented for all subjects in the Safety Analysis set for screening and all follow-up time 
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14.7 
Cranial Nerve Function  
Cranial nerve function physical examination will be performed for all subjects at 
screening, post-procedure and at all follow-up visits.  The change from baseline for 
subjects in the Safety Analysis set in each Group will be presented for all follow-up 
visits.  
15.0 Prior and Concomitant Medications 
Prior and concomitant medications including prescription and over-the counter drugs 
will be recorded for Groups A and B. Medications will be coded using the World 
Health Organization Drug Dictionary (WHO Drug) to identify the drug class and 
preferred drug name. 
 
Concomitant medications will include all medications that started on or after the 
procedure through the final study follow-up visit. Prior medications will include all 
medications that started within 28 days prior and stopped prior to the day of procedure. 
 
Prior and concomitant medication data will be presented in a data listing for safety 
subjects.  
 
 
 
 
 
 
  
 
17.0  Handling of Missing Data 
 
Missing data and the causes of the missing data will be summarized and presented. The 
number and proportion of subjects eligible for and compliant with all follow-up 
examinations will be presented. Subjects who withdraw from the study will be 
tabulated with the reasons for the withdrawal. Subjects who initiate the procedure, 
regardless of tolerability outcome or anesthesia effectiveness, will be encouraged to 
return for all follow-up assessments.  
 
Group A Primary Endpoint: If a subject in Group A discontinues iontophoresis prior to 
the TM tap assessment or declines TM tap assessments, the subject will provide a VAS 
pain score for the attempted procedure and will be included in the analysis of the 
primary endpoint. 
 
 
 
 Reasons for discontinuation will be 
documented and presented in the clinical study report. 
 






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21.0 Multiplicity Adjustment 
Groups A & B each have a single primary endpoint tested at a significance level of 
2.5%.  Each primary endpoint must pass the statistical test for the study to be 
considered successful.  The familywise error rate is therefore controlled at 2.5% and no 
multiplicity adjustments are planned. 
 
22.0 Data Listings 
Subject data will be summarized using listings and tables.  All electronic case report 
form (eCRF) data will be listed per subject for all enrolled subjects. All listings will 
include the subject number and the identification of the study Group and treatment for 
Group A only. 
 
 
 


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23.0 Definition of Variables 
 
23.1 
Baseline 
Baseline is defined as the last observation recorded prior to the treatment procedure.   
 
Age will be calculated in years and fractions of year based on the date of informed 
consent relative to date of birth.  
 
23.2 
Study Day Calculation 
Study Day 0 is the date of study procedure.  Study Day is calculated relative to Study 
Day 0 and will appear in the listings where applicable. 
Study Day will be calculated as: 
Study Day = Date of event– Date of study procedure 
Due to the acute nature of the study, no rules will be applied (eg, to assign missing day 
as 15th of month). Missing date data (day, month or year) will be queried. 
 
24.0 Other General Considerations 
Raw data will be presented with the exact precision that it was collected on the eCRF or 
other external data sources.   
 
Percentages will be reported with exactly one decimal place.  The mean and standard 
deviation as well as any corresponding confidence intervals will be reported with one 
decimal place. Blank fields on an eCRF will be displayed as blank fields in 
corresponding listings.   
 
25.0 References 
ICH harmonised tripartite guideline - Statistical principles for clinical trials (E9) – Step 
4, 05 Feb 1998. 
 
26.0 Appendix - Code 
    


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