Tympanoseal (Tympanic Membrane Device) Clinical Study
Conditions: Tympanic Membrane Perforation
Sponsor: Grace Medical, Inc.

Tympanoseal Clinical Study, 
NCT02918942 
Title: Tympanoseal (Tympanic Membrane Device) Clinical Study 
Number: NCT02918942 
Date: 7/12/2017 
Contents: Study Protocol. 

Protocol 2015.01 - Rev. B Tympanoseal Research Protocol, Grace Medical, Inc. Confidential 
 
Version Date: 07/12/2017  
 
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TYMPANOSEAL RESEARCH PROTOCOL 
GRACE MEDICAL, INC. 
 
 
 
Protocol Number 
2015.01 - Rev. B 
Version Date: 
07/12/2017 
Investigational Product: 
Tympanoseal 
Sponsor: 
Grace Medical, Inc. 
8500 Wolf Lake Drive 
Suite 110  
Memphis, TN 38133-4104 
 
 
Principal Investigator: 
Name:  
 
E-mail:  
 
 
 
 
Approval: 
 
 
 
Sponsor Signature (Name and Title)  
 
Date 
 
This confidential information about an investigational product is provided for the 
exclusive use of investigators of this product and is subject to recall at any time.  
The information in this document may not be disclosed unless federal or state law 
or regulations require such disclosure.  Subject to the foregoing, this information 
may be disclosed only to those persons involved in the study who have a need to 
know, with the obligation not to further disseminate this information.   

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PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study subjects enrolled under my supervision and 
providing Grace Medical, Inc. with complete and timely information, as outlined in the 
protocol.  It is understood that all information pertaining to the study will be held strictly 
confidential and that this confidentiality requirement applies to all study staff at this site. 
Furthermore, on behalf of the study staff and myself, I agree to maintain the procedures 
required to carry out the study in accordance with accepted GCP principles and to abide by 
the terms of this protocol. 
 
Protocol Number:  2015.01 – Rev. B 
 
Protocol Title:  Tympanoseal Research Protocol 
 
Protocol Date:  July 12, 2017 
 
 
 
 
Investigator Signature  
 
Date 
 
Print Name and Title 
Site # 
 
 
Site Name 
 
Address 
 
 
 
 
 
 
 
Phone Number  

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TABLE OF CONTENTS 
 
1 BACKGROUND .................................................................................................... 8 
      1.1  Overview of Non-Clinical Studies .................................................................. 8 
1.2 Overview of Clinical Studies .......................................................................... 12 
2 STUDY RATIONALE ............................................................................................. 12 
2.1 Risk / Benefit Assessment ............................................................................. 12 
3 STUDY OBJECTIVES ........................................................................................... 13 
3.1 Primary Objective .......................................................................................... 13 
3.2 Secondary Objectives ................................................................................... 13 
4 STUDY DESIGN .................................................................................................... 13 
5 CRITERIA FOR EVALUATION ............................................................................. 14 
5.1 Primary Efficacy Endpoint ............................................................................. 14 
5.2 Secondary Efficacy Endpoints ....................................................................... 14 
5.3 Safety Evaluations ........................................................................................ 14 
6 SUBJECT SELECTION ......................................................................................... 14 
6.1 Study Population ........................................................................................... 14 
6.2 Inclusion Criteria ........................................................................................... 14 
6.3 Exclusion Criteria .......................................................................................... 14 
7 CONCOMITANT MEDICATIONS .......................................................................... 15 
7.1 Allowed Medications and Treatments ............................................................ 15 
7.2 Prohibited Medications and Treatments ........................................................ 15 
8 STUDY TREATMENTS ......................................................................................... 15 
8.1 Blinding / Randomization ............................................................................... 15 
8.2 Formulation of Tympanoseal ......................................................................... 15 
8.3 Packaging and Labeling ................................................................................ 16 
8.4 Device Usage ................................................................................................ 16 
8.5 Dispensing .................................................................................................... 16 
8.6 Instructions for Use ....................................................................................... 16 
8.7 Supply of Study Device at the Site ................................................................ 17 
8.8 Study Device Accountability .......................................................................... 17 
8.9 Measures of Treatment Compliance.............................................................. 17 
9 STUDY PROCEDURES AND GUIDELINES ......................................................... 17 
9.1 Clinical Assessments .................................................................................... 18 
10 EVALUATIONS BY VISIT ..................................................................................... 18 
10.1 Enrollment / Pre-operative Visit   ................................................................... 18 
10.2 Day of Procedure  ......................................................................................... 19 
10.3  Same Day Enrollment and Procedure……………………………………………19 
10.4 Follow-up Evaluation - 4 weeks ..................................................................... 19 
10.5 Follow-up Evaluation - 10 weeks ................................................................... 20 
10.6 Follow-up Evaluation - 16 weeks ................................................................... 20 

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10.7 Potential Additional Follow-Ups …………………………………….……………20 
10.8 Unscheduled Visit(s)……………………………………………………………….21 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION ....................... 21 
11.1 Adverse Events ............................................................................................. 21 
11.2 Serious Adverse Event (SAE) ....................................................................... 22 
11.3 Serious Adverse Event Reporting ................................................................. 23 
11.4 Unanticipated Adverse Device Effects ........................................................... 23 
12  DISCONTINUATION AND REPLACEMENT OF SUBJECTS ............................... 23 
12.1 Early Discontinuation .................................................................................... 23 
12.2 Withdrawal of Subjects from the Study .......................................................... 24 
12.1 Replacement of Subjects .............................................................................. 24 
13 PROTOCOL DEVIATIONS .................................................................................... 24 
14 STATISTICAL METHODS AND CONSIDERATIONS ........................................... 24 
14.1 Sample Size and Randomization .................................................................. 24 
15 DATA COLLECTION, RETENTION AND MONITORING ...................................... 25 
15.1 Data Collection Instruments .......................................................................... 25 
15.2 Availability and Retention of Investigational Records .................................... 25 
15.3 Monitoring ..................................................................................................... 25 
15.4 Subject Confidentiality ................................................................................... 27 
16 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS ................... 27 
16.1 Protocol Amendments ................................................................................... 27 
16.2 Institutional Review Boards  .......................................................................... 28 
16.3 Informed Consent Form ................................................................................ 28 
16.4 Publications ................................................................................................... 29 
16.5 Investigator Responsibilities .......................................................................... 29 
 
APPENDIX 1  SCHEDULE OF STUDY VISITS ........................................................... 30  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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List of Abbreviations 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
PI 
Principal Investigator 
SAE 
Serious Adverse Event 
UADE 
Unanticipated Adverse Device Effect 
 
 

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PROTOCOL SYNOPSIS 
 
TITLE 
Tympanoseal Research Protocol 
SPONSOR 
Grace Medical, Inc. 
NUMBER OF SITES 
2 
RATIONALE 
This investigational clinical study is to assess the safety of 
Tympanoseal, a sodium/calcium alginate tympanic membrane 
perforation device that acts as a scaffold during the healing process.  
It is intended for use following removal or extrusion of indwelling 
tympanostomy tubes or traumatic injury of the tympanic membrane. 
 
STUDY DESIGN 
This is a non-randomized, non-blinded study. 
 
PRIMARY OBJECTIVE 
The purpose of this investigational study is to assess the safety of 
Tympanoseal when used during the healing process. 
SECONDARY 
OBJECTIVES 
Determine if any adverse events occur during presence of material 
on tympanic membrane. 
NUMBER OF 
SUBJECTS 
Up to 15 at each site 
SUBJECT SELECTION 
CRITERIA 
Inclusion Criteria: 
1) Male or female patients over 2 years of age at enrollment 
2) Documentation of a retained tympanostomy tube or persistent 
perforation less than 5 mm. 
3) Written informed consent (and assent when applicable) obtained 
from subject or subject’s legal guardian and ability for subject to 
comply with the requirements of the study 
 
Exclusion Criteria: 
1) Active otorrhea or otitis media 
2) History of cholesteatoma 
3) Perforations on the edge of the tympanic membrane  
4) Presence of a condition or abnormality that in the opinion of the 
Investigator would compromise the safety of the patient or the quality 
of the data 
5) Subject is taking systemic/oral corticosteroids  
6) Subject will require the continued use of any type of topical otic 
medication to the ear(s) with Tympanoseal. 
 
RESEARCH PRODUCT  
Tympanoseal will be placed during a surgical procedure. 

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DURATION OF 
SUBJECT 
PARTICIPATION  
AND  
DURATION OF STUDY 
Subjects may be in study for up to 36 weeks.  Subjects may exit 
study at any follow-up visit if healing is noted by investigator. 
 
It is expected that there will be up to 3 follow-up visits after surgery: 
4 weeks (+ 7 days)  
10 weeks (+ 7 days) 
16 weeks (+ 14 days)    
However, additional follow-up visits may be scheduled (until no 
product remains visible) at 20 weeks (+ 14 days), 24 weeks (+ 14 
days), 30 weeks (+ 14 days), 36 weeks (+ 14 days).  Subjects may 
exit study at any interval after Tympanoseal device is no longer 
present.  Additional visits may also be scheduled per investigator 
discretion.  
 
Estimated total duration of the study is expected to be 18 months 
from subject recruitment to final subject follow-up. 
 
CONCOMITANT 
MEDICATIONS 
 
Prohibited:  
Chronic systemic/oral corticosteroids 
 
 
Topical medications for the ear unless medically  
 
 
 
necessary 
EFFICACY 
EVALUATIONS 
Otomicroscopy with photograph of tympanic membrane at each 
Follow-Up Visit until Study Exit 
PRIMARY ENDPOINT 
 
Healing of Tympanic Membrane  
SECONDARY 
ENDPOINTS 
Resorption of Tympanoseal 
SAFETY 
EVALUATIONS 
 
Examination during follow-up visits will establish an incidence of 
adverse events to the implantation of Tympanoseal 
PLANNED INTERIM 
ANALYSES  
Due to short time-frame of this study, no interim analyses are 
planned.  Serious adverse events will be monitored on an ongoing 
basis throughout the study. 
 
STATISTICS 
 
 
As this study is for safety and utilizing a small number of subjects, no 
statistical analysis will be completed.  Information will be presented to 
the FDA in tabular format. 
 
RATIONALE FOR 
NUMBER OF 
SUBJECTS 
Suggested by the FDA during pre-510(k) conference call. 

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1 
BACKGROUND 
The purpose of this investigational study is to assess the ability of Tympanoseal 
(sodium/calcium alginate), an investigational device, to act as a scaffold during healing of 
the tympanic membrane.  Tympanoseal is intended for use following removal or extrusion of 
indwelling tympanostomy tubes or traumatic injury of the tympanic membrane.   
 
 
Formulation of Tympanoseal  
 
Tympanoseal is formulated from a hydrogel consisting of sodium and calcium mixed salt of 
alginic acid. 
 
Grace Medical, in cooperation with Cliff Megerian MD of Case Western Reserve University 
has developed Tympanoseal, a sodium/calcium alginate tympanic membrane scaffolding 
device to address the issues in existing state of the art technologies.  It will be available as 
one device that can be trimmed to four different sizes.  
 
Tympanoseal devices were constructed using an injection molding 
technique which results in gels composed of 2.7% PronovaTM calcium 
alginate and 1.8% PronovaTM sodium alginate (Melvik et al., United States 
Patent 7,790,600, September 7,2010). This gelling methodology is 
proprietary to NovaMatrix, AS of Drammen, NO, and is marketed as a self-
gelling alginate. Upon solidification the hydrogel appears very light, 
opaque beige.  
 
Different sizes as measured by the diameter of the inter-flange shaft will be available 
including 2mm, 3mm, 4mm and 5mm.  Tympanoseal will be provided lyophilized in a special 
capsule made of medical-grade transparent Nylon 12 which has been proven to be both 
sterilizable and non-contaminating to medical devices.  The device is removed by breaking 
tabs on the bottom section, taking off the top section and removing the contents with 
forceps.  The product comes in a Christmas tree shape.  The physician selects the correct 
size and removed by cutting what is not needed. 
 
 
1.1 
Overview of Non-Clinical Studies 
Review of Grace Medical Tympanoseal Sodium/Calcium Alginate Seal Test Data 
 
Hott ME, Megerian CA, Beane R, Bonassar LJ. Fabrication of tissue engineered tympanic 
membrane patches using computer-aided design and injection molding.  
Laryngoscope. 2004 Jul; 114(7):1290-5. 
 
Chronic tympanic membrane perforation patches were fabricated by molding alginate 
loaded with bovine articular chondrocytes into a bobbin-shaped construct. Chondrocytes 
were cultured for 10 weeks and assessed for mechanical and dimensional stability. 
Extracellular matrix was continually deposited and was rich in collagen and proteoglycans. 
 
Weber DE, Semaan MT, Wasman JK, Beane R, Bonassar LJ, Megerian CA. Tissue-
engineered calcium alginate patches in the repair of chronic chinchilla tympanic membrane 
perforations.   
Laryngoscope. 2006 May;116(5):700-4. 

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The publication describes the comparison of alginate hydrogel grafts versus application of a 
paper patch in a chinchilla model of tympanic membrane perforation.  The alginate treated 
perforations demonstrated significantly improved healing rates over both the untreated 
control group and the paper patch control group.  Nine of thirteen healed in the alginate 
group, two of nine in the paper patch group and one of eleven in the control group.  It was 
concluded that calcium alginate tympanic grafts offer significant advantages in the treatment 
of chronic tympanic membrane perforations over traditional methods. 
 
 
Biocompatibility Test Data 
Tympanoseal (sodium/calcium alginate scaffold) is deemed to be biocompatible and 
presents no infection risk in humans.  Results of testing are summarized below.  
Biocompatibility tests were performed with NovaMatrix sodium and calcium alginates used 
to fabricate Tympanoseal. 
Test Material 
Biocompatibility 
Test 
Test Source 
Results 
LVG PronovaTM 
Sodium Alginate 
Cytotoxicity based on 
in vitro cell culture of 
3T3 mouse fibroblasts 
and V79 Chinese 
hamster 
NovaMatrix Drug 
Master File 14993 
No effects on cell 
survival or ability to form 
colonies. 
LVG PronovaTM 
Sodium Alginate (132 
mPas viscosity) 
Acute systemic toxicity 
by intraperitoneal route 
mouse 
NovaMatrix Drug 
Master File 14993 
No mortaility or 
abnormal clinical signs 
with normal weight gain 
LVG PronovaTM 
Sodium Alginate (132 
mPas viscosity) 
Acute systemic toxicity 
by intraperitoneal route 
rat 
NovaMatrix Drug 
Master File 14993 
No mortaility or 
abnormal clinical signs 
with normal weight gain 
LVG PronovaTM 
Sodium Alginate (30 
mPas viscosity) 
Acute systemic toxicity 
by intraperitoneal route 
rat 
NovaMatrix Drug 
Master File 14993 
No mortaility or 
abnormal clinical signs 
with normal weight gain 
LVG PronovaTM 
Sodium Alginate 3.5 
mPas viscosity) 
Acute systemic toxicity 
by intraperitoneal route 
rat 
NovaMatrix Drug 
Master File 14993 
No mortaility or 
abnormal clinical signs 
with normal weight gain 
LVG PronovaTM 
Sodium Alginate 
Hemolysis 
NovaMatrix Drug 
Master File 14993 
No lysis of blood cells 
recorded 
LVG PronovaTM 
Sodium Alginate 
Implantation in rabbits 
NovaMatrix Drug 
Master File 14993 
Moderate inflammatory 
responses with no 
implant material 
remaining at site of 
implantation. Slightly 
greater tissue reaction 
was observed than at 
the sham operation site. 
 
LVG PronovaTM 
Calcium Alginate 
Cytotoxicity based on 
in vitro cell culture of 
3T3 mouse fibroblasts 
NovaMatrix Drug 
Master File 20497 
Material had no 
cytotoxic effects on 
either cell lines 

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and V79 Chinese 
hamster 
LVG PronovaTM 
Calcium Alginate 
Acute systemic toxicity 
rats, s.c. 
NovaMatrix Drug 
Master File 20497 
No evidence of toxicity 
LVG PronovaTM 
Calcium Alginate 
Acute systemic toxicity 
rats, i.m. 
NovaMatrix Drug 
Master File 20497 
No evidence of toxicity 
LVG PronovaTM 
Calcium Alginate 
Subchronic toxicity 
Sprague Dawley rats, 
Charles River 
Laboratory 
NovaMatrix Drug 
Master File 20497 
No signs of toxic effects 
and no weight loss over 
study period 
LVG PronovaTM 
Calcium Alginate 
LD50 i.p. in rats 
NovaMatrix Drug 
Master File 20497 
1,407 mg/kg lethal dose 
in rats 
 
LVG PronovaTM 
Calcium Alginate 
LD50 i.v. in rats 
NovaMatrix Drug 
Master File 20497 
64 mg/kg lethal dose in 
rats 
LVG PronovaTM 
Calcium Alginate 
Rat implantation, 
dorsal left scapula of 
calcium alginate slurry 
in normal saline 
NovaMatrix Drug 
Master File 20497 
No signs of systemic 
toxicity, granulomas in 
two animals, foreign 
body reaction shortly 
after implantation 
NovaMatrix self 
gelling 
sodium/calcium 
alginate gel 
Rat implantation, 
dorsal right scapula 
and hindlimb of self 
gelling sodium/calcium 
alginate in normal 
saline  
NovaMatrix Drug 
Master File 20497 
No adverse systemic 
signs, no weight change 
and gelatinous 
thickening at the 
injection site days 3, 15, 
31 and 60. 
NovaMatrix self 
gelling 
sodium/calcium 
alginate gel 
Rat subcutaneous 
injection 
NovaMatrix Drug 
Master File 20497 
No adverse toxic effects 
recorded, day 3 
revealed cell infiltration, 
days 15 and 60 foreign 
body reaction 
NovaMatrix self 
gelling 
sodium/calcium 
alginate gel 
Rat intramuscular 
injection 
NovaMatrix Drug 
Master File 20497 
No adverse toxic effects 
recorded, day 3 
revealed cell infiltration, 
days 15 and 60 foreign 
body reaction 
NovaMatrix self 
gelling 
sodium/calcium 
alginate gel, as 
manufactured for 
Grace Medical 
ISO MEM elution using 
L-929 mouse fibroblast 
cells 
WuXi Apptec report to 
Grace Medical, Inc. 
Test article is not 
considered cytotoxic 
according to the 
conditions of this test. 
NovaMatrix self 
gelling 
sodium/calcium 
alginate gel, as 
manufactured for 
Grace Medical 
ISO intracutaneous 
irritation test 
WuXi Apptec report to 
Grace Medical, Inc. 
Score of 1 according to 
ISO protocols, was not 
irritating 

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Ototoxicity testing of calcium alginate samples using Grace Medical’s proprietary method 
was performed by Dr. Hinrich Staecker and Jennifer Nelson Brantley of the University of 
Kansas Medical Center.  The Auditory & Vestibular Neuroscience Lab tested the ototoxicity 
by using an in- mouse model when exposed to Grace Medical’s alginate formulation via 
surgical implantation.   
 
Conclusions:  “There was no evidence of any hearing loss either in the acute or late period 
after alginate placement. No evidence of balance problems were seen on behavioral 
evaluation. Evaluation of animals after termination of experiment demonstrated that all the 
material had absorbed.” 
 
 
 
 
NovaMatrix self 
gelling 
sodium/calcium 
alginate gel, as 
manufactured for 
Grace Medical 
ISO Guinea pig 
maximization 
sensitization test, 2 
extracts 
WuXi Apptec report to 
Grace Medical, Inc. 
Under the conditions of 
this protocol the test 
article did not elicit a 
sensitization response. 
NovaMatrix self 
gelling 
sodium/calcium 
alginate gel, as 
manufactured for 
Grace Medical 
ISO In vivo mouse 
micronucleus assay 
WuXi Apptec report to 
Grace Medical, Inc. 
The test article is 
considered non-
mutagenic in this test 
system. 
NovaMatrix self 
gelling 
sodium/calcium 
alginate 
ISO mouse lymphoma 
with extended 
treatment 
WuXi Apptec report to 
Grace Medical, Inc. 
Test article was found to 
be non-mutagenic (non-
genotoxic and non-
clastogenic) 
NovaMatrix self 
gelling 
sodium/calcium 
alginate 
ASTM Hemolysis 
Assay-Direct Contact 
and Extraction Method 
WuXi Apptec report to 
Grace Medical, Inc. 
Test material was not 
hemolytic 
NovaMatrix self 
gelling 
sodium/calcium 
alginate 
Complement Activation 
C3a and SC5b-9 
WuXi Apptec report to 
Grace Medical, Inc. 
Test article did not 
activate complement 
more than control 
NovaMatrix self 
gelling 
sodium/calcium 
alginate 
ISO In Vivo Mouse 
Micronucleus Assay 
WuXi Apptec report to 
Grace Medical, Inc. 
Test article was not 
genotoxic 
NovaMatrix self 
gelling 
sodium/calcium 
alginate 
ISO Bacterial 
Mutagenicity Test-
Ames Assay 
WuXi Apptec report to 
Grace Medical, Inc. 
Test article was not 
mutagenic 

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1.2 
Overview of Clinical Studies 
 
Adverse Events Associated with NovaMatrix Self Gelling Alginate 
 
Clinical trials of Algisyl (Lone Star Heart, Laguna Hills, CA) a cardiac repair gel made with 
NovaMatrix self gelling alginate have demonstrated adverse events in 21.4% of test 
subjects.  None of these events have been related to alginate itself but to development of 
infections or worsening of heart conditions  No other occurrences of adverse events from 
use of NovaMatrix self gelling alginate have been found. 
 
 
2 
STUDY RATIONALE 
 
This study will provide data on the safety and the ability of sodium/calcium alginate gels to 
act as a scaffold capable of occluding a tympanic membrane perforation over the duration 
of complete healing.  Tympanoseal could be used in cases where cartilage or fat graft 
tympanoplasty would be indicated. 
 
 
2.1 
Risk / Benefit Assessment 
 
Risk Versus Benefits to the Subjects 
 
Risk levels are assessed on the severity level and the likelihood of occurrence.  Both 
severity and occurrence levels for the risks assessed were considered low in this study. 
 
 
Risk 
Risk 
Level 
Mitigation 
Bio-incompatible – adverse reaction to the 
tympanic membrane 
Low 
Biocompatibility tests 
Insufficient coverage of the TM perforation 
Low 
Range of Calcium alginate seal 
size available up to 5 mm 
TM perforation does not fully repair / 
enlarges 
Low 
Results of Chinchilla study 
Sclerosis of the TM 
Low 
Results of Chinchilla study 
Granulation tissue remains resulting in 
delayed healing 
Low 
Results of Chinchilla study 
Hemorrhage of TM 
Low 
Results of Chinchilla study 
Hearing loss either poor or worsens 
Low 
Results of Chinchilla study 
Lateral Displacement of Material 
Low 
Operative Technique indicates 
that larger flange is placed 
laterally. 
 
 

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The anticipated benefits of Tympanoseal are as follows: 
 
1. Potential improvement in perforation repair rate indicated by chinchilla study. 
 
2. Calcium alginate has been proven to increase fibroblast proliferation needed to produce 
collagen in the creation of a stable lamina propria layer.  No current perforation seal repair 
material enables regeneration of the natural lamina propria. 
 
3. Ease of application which will be similar to vent tube placement.  
 
4. Calcium ions in the seal will exchange for sodium ions in exudates of the tympanic 
membrane wound potentially enhancing hemostasis and allowing collagen deposition to 
establish a stable lamina propria. 
 
5. No risk of lateralization found in underlay techniques of tympanoplasty which may result 
in hearing loss and cholesteatoma. 
(Jung TT, Park SK. Mediolateral graft tympanoplasty for anterior or subtotal tympanic 
membrane perforation.  Otolaryngol Head Neck Surg . 2005 Apr;132(4):532-6). 
 
6. No need for Gelfoam to be placed under the seal to support it and eliminates the risk of 
fibrosis in the middle ear reported with Gelfoam.   
(Smith J,  Gardner E,  Dornhoffer JL.Hearing results with a hydroxylapatite/titanium bell 
partial ossicular replacement prosthesis.  Laryngoscope. 2002 Oct;112(10):1796-9.) 
 
7. Supplying surgeons with an FDA approved device to act as scaffolding for tympanic 
membrane perforation repair.  Currently all other products act as simple films and do not 
occlude a perforation. 
 
The potential benefits described outweigh the low level of risk. 
 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective is to assess the safety of Tympanoseal when used as scaffolding 
during the healing process.  
 
3.2  
Secondary Objectives 
The secondary objective is to determine ability / if any adverse events arise from 
implantation of Tympanoseal such as colonization by microorganisms or diminution of 
hearing by damping of tympanic membrane vibrations. 
 
4 
STUDY DESIGN 
This study will be a non-blinded, non-randomized trial.  There will be two (2) sites with a 
limit of fifteen (15) subjects at each site. (Up to thirty (30) total subjects are planned.)  Each 
subject will have Tympanoseal placed during a surgical procedure.   

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Evaluations will be taken at baseline and up to three evaluations at 4, 10 and 16 weeks.  If 
tympanic healing is noted at any visit, then the subject may exit the study without need for 
additional follow-up evaluations. 
 
Screening data will be reviewed to determine subject eligibility.  Subjects who meet all 
inclusion criteria and none of the exclusion criteria will be entered into the study.  All 
subjects will be treated with surgically implanted Tympanoseal, either unilaterally or 
bilaterally as needed. 
 
Total duration of subject participation will be up to 16 weeks post-procedure and total study 
duration is estimated to be 6 months. 
 
5 
CRITERIA FOR EVALUATION 
 
5.1 
Primary Efficacy Endpoint 
The primary endpoint will be the healing of the tympanic membrane perforation. In 
chinchillas this occurred between 1 and 2 months. 
 
5.2  
Secondary Efficacy Endpoints 
Secondary study endpoint at 16 weeks will establish that the Tympanoseal has fully 
resorbed and is no longer visible. 
 
5.3  
Safety Evaluations 
Examination during follow-up visits will establish an incidence of adverse events to the 
implantation of Tympanoseal. 
 
6 
SUBJECT SELECTION 
 
6.1 
Study Population 
Subjects with retained tympanostomy tube(s) or persistent central tympanic perforation of 
less than 5mm will be enrolled in this study. 
 
6.2 
Inclusion Criteria 
 
1. Male or female patients over 2 years of age at enrollment. 
2. Documentation of a retained tympanostomy tube or persistent perforation less than 
5 mm. 
3. Written informed consent (and assent when applicable) obtained from subject or 
subject’s legal guardian and ability for subject to comply with the requirements of the 
study. 
 
6.3 
Exclusion Criteria 
 
1. Active otorrhea or otitis media 
2. History of cholesteatoma 
3.  Perforations on the edge of the tympanic membrane.  
4. Presence of a condition or abnormality that in the opinion of the Investigator would 
compromise the safety of the patient or the quality of the data. 
5.  Subject is taking systemic/oral corticosteroids 
6. Subject will require the continued use of any type of topical otic medication to the 
 
ear with Tympanoseal 

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7  
Concomitant Medications 
 
All subjects should be maintained on the same medications throughout the entire study 
period, as medically feasible, with no introduction of new chronic therapies. 
 
7.1 
Allowed Medications and Treatments 
 
Standard therapies are allowed except for treatments noted in the exclusion criteria 
described above and as noted in the prohibited medications section below.  
 
7.2 
Prohibited Medications and Treatments 
 
The following medications are prohibited during the study and administration will be 
considered a protocol violation: 
1.  Systemic/oral corticosteroids  
2.  Use of any topical medication to the ear immediately following surgery. 
 
 
Articles that justify the prevention of the use of systemic corticosteroids are provided below.   
 
Kaftan H. Hosemann W.    Topical Application of Mitomycin C in Combination with 
Dexamethasone: Effective Delay of Myringotomy closure.   
ORL J Otorhinolaryngol Relat Spec. 2006;68(4):185-8. 
 
Kaftan H, Hosemann W.    Systemic Corticoid Application in Combination with Topical 
Mitomycin or Dexamethosone:  Inhibition of Wound Healing after Tympanic Membrane 
Perforation.   
HNO. 2005 Sep;53(9):700-83. 
 
 
8 
STUDY TREATMENT  
 
All subjects will receive the investigational device, Tympanoseal. 
 
8.1 
Blinding / Randomization 
 
This is a non-blinded, non-randomized study. 
 
8.2 
Formulation of Tympanoseal  
 
Tympanoseal is formulated from a hydrogel consisting of sodium and calcium mixed salt of 
alginic acid.  The sodium/calcium alginate devices were constructed using an injection 
molding technique which results in gels composed of 2.7% PronovaTM calcium alginate and 
1.8% PronovaTM sodium alginate (Melvik et al., United States Patent 7,790,600, September 
7,2010). This gelling methodology is proprietary to NovaMatrix, AS of Drammen, NO, and is 
marketed as a self-gelling alginate.  Additional information was provided in Section 1. 
 
 

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8.3 
Packaging and Labeling 
Packaging: 
Tympanoseal is provided sterile in a protective, transparent nylon capsule inside a 
transparent moisture barrier pouch. 
 
Labeling:   
Each package of study device will be labeled with the required FDA warning statement, the 
catalog and lot numbers, the name of the sponsor, and directions for patient use and 
storage.  Instructions for Use will also be included. 
 
8.4 
Device Usage 
One device will be used per treated tympanic membrane. 
8.5 
Dispensing 
The approved investigator at the site will store the device and control the use of the test 
article. 
8.6 
Instructions for Use 
Operative Technique 
This technique description is the suggested treatment for the uncomplicated procedure. The 
preferred treatment is that which addresses the needs of the specific patient.  The 
perforation site is evaluated under the operating microscope and the edges of the 
perforation are manipulated with a small pick so as to freshen the margins of the 
perforation.  
 
A perforation sizing device will be provided with each device which will allow the surgeon to 
estimate the diameter of a hole in the tympanic membrane in order to choose a repair 
construct of appropriate size. 
 
The lyophilized device is provided in a protective capsule with four sizes each attached to 
the other with progressively smaller flanges along its length.  The capsule is opened by 
bending the lateral tabs on its larger bottom portion with one hand while carefully removing 
the smaller top portion with the other hand.  The device can be easily extracted with 
forceps. 
 
The proper size for a given perforation is excised with surgical scissors or scalpel.  One 
flange will be of a larger diameter than the other; the surgeon will implant the device with 
the larger flange laterally.  Insertion of Tympanoseal is similar to the placement of a 
tympanostomy tube.  Immediately after insertion normal saline should be instilled in the 
external auditory canal to swell the device and completely occlude the perforation. 
 
After Tympanoseal is in place, wax earplugs should be in place during showers and 
swimming. 
 
 
 
 

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8.7 
Supply of Study Device at the Site 
 
The Sponsor will ship Study Device to the investigational sites.  The initial study device 
shipment will be made after site activation (i.e., all required regulatory documentation has 
been received by the Sponsor and a contract has been executed). Subsequent study device 
shipments will be made at site request for resupply. 
8.8  
Study Device Accountability 
Study devices should be stored by the study site at room temperature.  
An accurate and current accounting of the dispensing of study devices will be maintained on 
an ongoing basis by a member of the study site staff.  The number of study devices 
received and used will be recorded on the Investigational Device Accountability Record.  
The study monitor will verify these documents throughout the course of the study. 
8.9 
Measures of Treatment and Compliance 
Subjects are required to return for follow-up visits.  Each will be instructed to contact 
investigator’s office for questions or need for unscheduled visit. 
 
9 
STUDY PROCEDURES AND GUIDELINES 
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and 
dated by the subject or subject’s legal guardian  If appropriate, assent must also be 
obtained prior to conducting any study-related activities. 
The preoperative visit will include a medical history, physical examination, prior ENT history, 
concomitant medications and otomicroscopy with photograph of the tympanic membrane 
perforation prior to use of Tympanoseal.  A photograph will also be taken after product has 
been inserted. 
Subjects enrolled in the study will be required to return for up to three follow-up evaluations 
after surgery at 4 weeks, 10 weeks and 16 weeks.  If tympanic healing is noted at any visit, 
then the subject may exit the study without need for additional follow-up evaluations.   
It is expected that the product will have resorbed (dissolved) prior to 16 weeks.  However, if 
Tympanoseal is visible at the 16 week visit, the subject should have additional follow-up 
visits scheduled until no product remains at 20 weeks (+ 14 days), 24 weeks (+ 14 days), 
and 36 weeks (+ 14 days).   Subjects may exit study at any interval when Tympanoseal is 
no longer present.  Additional visits may be scheduled per investigator discretion. 
  
If the Tympanoseal product appears ‘dry’ to the Investigator, 3-5 drops of saline may be 
added to keep it moist.  (This should be noted in the comments section of the CRF.) 
 

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9.1 
Clinical Assessments 
9.1.1 Concomitant Medications 
All concomitant medications and concurrent therapies will be documented at enrollment, 
day of procedure, post-operative follow-up visits, and study exit.  Dose, unit frequency of 
administration, and indication for administration and dates of medication will be captured. 
9.1.2 Demographics  
Demographic information (date of birth, gender, race) will be recorded at enrollment. 
9.1.3 Medical History  
Relevant medical history, including prior ENT history, cause and size of perforation and 
length of time present, allergies, other pertinent respiratory history, and information 
regarding underlying diseases will be recorded at Enrollment. 
9.1.4 Physical Examination 
A physical examination will be performed by either the investigator or a sub-investigator 
who is a physician at enrollment.  Qualified staff (MD, NP, RN, and PA) may complete an 
abbreviated physical exam at all other visits.  New abnormal physical exam findings must 
be documented and will be followed by a physician or other qualified staff at the next 
scheduled visit. 
9.1.5 Vital Signs 
Body temperature, pulse and respirations will be recorded at each visit.  Height and weight 
will also be obtained. 
9.1.6 Otomicroscopy with Photograph of Tympanic Membrane 
At each visit otomicroscopy with photograph of tympanic membrane is required. 
9.1.7 Adverse Events 
Information regarding occurrence of adverse events will be captured from procedure date to 
study completion.  Duration (start and stop dates), severity/grade, outcome, treatment and 
relation to study device will be recorded on the Adverse Event Tracking Log. 
 
10 
EVALUATIONS BY VISIT 
Please note that it is acceptable for the Enrollment and Procedure to occur on the 
same day.  Duplicate tasks do not need to be performed and duplicate CRFs are not 
required to be completed.  See section 10.3 for additional information. 
10.1 
Enrollment / Pre-operative Visit   
1. Review the study with the subject (subject’s legal guardian) and obtain written informed 
consent and HIPAA authorization and assent, if appropriate. 
2. Assign the subject a unique screening number. 
3. Record demographics data. 

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4. Record general medical history and prior ENT history including the cause and size of 
perforation and length of time present, allergies, and other pertinent respiratory history. 
5. Record concomitant medications.** 
6. Perform physical examination, including vital signs.** 
7. Otomicroscopy with photograph of tympanic membrane prior to procedure.** 
8. Schedule subject for surgical procedure. 
 
10.2 
Day of Procedure  
1. Concomitant medications review.*** 
2. Perform abbreviated physical examination.*** 
3. Perform and record vital signs.*** 
4.  Completion of Procedure and Device Information CRF. 
5.  Otomicroscopy with photograph of tympanic membrane after procedure with 
Tympanoseal in place.** 
6. If applicable, record any Adverse Events. 
**Note:   See information below if enrollment and procedure are on the same 
day. 
 
10.3  If Enrollment and Procedure are on the same day, the following tasks and 
CRFs are required to be completed. 
1. Review the study with the subject (subject’s legal guardian) and obtain written informed 
consent and HIPAA authorization and assent, if appropriate. 
2. Assign the subject a unique screening number. 
3. Record demographic data. (Enrollment / Demographics CRF) 
4.  Complete Eligibility Criteria CRF 
5. Record general medical history and prior ENT history including the cause and size of 
perforation and length of time present, allergies, and other pertinent respiratory history. 
(Medical History (General) and ENT History CRF’s) 
6. Record concomitant medications. (Concomitant Medication CRF) 
7. Perform physical examination, including vital signs. (Pre-Procedure Visit CRF) 
8. Otomicroscopy with photograph of tympanic membrane prior to procedure. 
9.  Completion of Procedure and Device Information CRF. 
10. Otomicroscopy with photograph of tympanic membrane after procedure with 
Tympanoseal in place. 
12. If applicable, record any Adverse Events. 
 
10.4 
Follow-up Evaluation - 4 weeks (+ 7 days) 
1. If applicable, record any new Adverse Events.  
2. Record changes to concomitant medications. 

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3. Perform abbreviated physical examination. 
4. Perform and record vital signs. 
5. Otomicroscopy with photograph of tympanic membrane 
Note:  If complete healing is noted, then patient may exit the study and Subject 
Study CRF should be completed. 
 
10.5 
Follow-up Evaluation - 10 weeks (+ 7 days) 
1. If applicable, record any new Adverse Events.  
2. Record changes to concomitant medications. 
3. Perform abbreviated physical examination. 
4. Perform and record vital signs. 
5. Otomicroscopy with photograph of tympanic membrane 
Note:  If complete healing is noted, then patient may exit the study and Subject 
Study CRF should be completed. 
 
10.6 
Follow-up Evaluation - 16 weeks (+ 14 days) (and additional visits as 
applicable.  See 10.7). 
1. If applicable, record any new Adverse Events. 
2. Record changes to concomitant medications. 
3. Perform abbreviated physical examination. 
4. Perform and record vital signs. 
5. Otomicroscopy with photograph of tympanic membrane 
Note:  If complete healing is noted, then patient may exit the study and Subject Study 
CRF should be completed. 
 
10.7 Potential Additional Follow-Ups at 20 weeks (+ 14 days), 24 (+ 14 days), 30 (+ 
14 days), 36 weeks (+ 14 days) as needed.  
 
It is expected that the Tympanoseal will have resorbed prior to 16 weeks.  However, 
additional visits should be scheduled for 20 weeks, 24 weeks, 30 weeks and 36 weeks 
until no product remains.  The subject may exit the study at any of these intervals after the 
device is no longer present. 
1. If applicable, record any new Adverse Events. 
2. Record changes to concomitant medications. 
3. Perform abbreviated physical examination. 
4. Perform and record vital signs. 
5. Otomicroscopy with photograph of tympanic membrane 

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Note:  If complete healing is noted, then patient may exit the study and Subject Study CRF 
should be completed. 
Unscheduled Visit CRF pages will be used to capture 20, 24 and 30 week follow-ups, 
if needed. 
 
10.8 
Unscheduled Visit(s) 
1. If applicable, record any new Adverse Events.  
2. Record changes to concomitant medications. 
3. Perform complete physical examination, record vital signs, and study evaluations. 
4. Otomicroscopy with photograph of tympanic membrane 
5. Please note the reason for the visit in the comments section. 
Note:  If complete healing is noted at this visit, the patient may exit the study 
and Subject Study CRF should be form completed. 
 
11 
ADVERSE EVENT REPORTING AND DOCUMENTATION 
11.1 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a 
medical device and that does not necessarily have a causal relationship with the treatment.  
An AE is therefore any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the administration of an 
investigational product, whether or not related to that investigational product.   
The Investigator will determine with the subject, the occurrence of AEs during each subject 
visit and record the information in the site’s source documents.  Adverse events will be 
recorded in the patient CRF.  Adverse events will be described by duration (start and stop 
dates and times), severity, outcome, treatment and relation to study device, or if unrelated, 
the cause.   
 
AE Severity Grading 
The guidelines below should be used to grade severity.  It should be pointed out that the 
term “severe” is a measure of intensity and that a severe AE is not necessarily serious. (A 
‘severe’ headache may not be a ‘severe’ AE.) 
The collection period for all AEs will begin after device is implanted and ends at Subject 
Exit. 
 

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AE Severity Grading 
Severity  
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of 
the sign or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy 
required,, hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as 
it occurred. This does not refer to an experience that 
hypothetically might have caused death if it were more severe. 
 
AE Relationship to Study Device 
The relationship of an AE to the study device should be assessed using the following the 
guidelines. 
Relationship 
to Device 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable 
temporal sequence from use of the device; that follows a known or expected 
response pattern 
Probably 
An event that follows a reasonable temporal sequence from use of device; 
that follows a known or expected response pattern and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state or by 
other interventions. 
Possibly 
An event that follows a reasonable temporal sequence from use of the 
device; that follows a known or expected response; but that could readily 
have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the 
study device. 
11.2 
Serious Adverse Event (SAE) 
An SAE is defined as any AE occurring that results in any of the following outcomes: 
1.  Death 
2.  A life-threatening adverse experience 
3.  An inpatient hospitalization or prolongation of existing hospitalization 
4.  A persistent or significant disability/incapacity 
5.  A congenital anomaly/birth defect  
6.  Required Intervention to Prevent Permanent Impairment or Damage  
 

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Emergency room visits that do not result in admission to the hospital should be evaluated 
for one of the other serious outcomes (e.g., life-threatening; required intervention to prevent 
permanent impairment or damage; other serious medically important event). 
 
 
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the subject or require intervention to prevent 
one of the outcomes listed.  
11.3 
Serious Adverse Event Reporting 
Study sites will document all SAEs that occur (whether or not related to study device).  The 
collection period for all SAEs will begin after device is implanted and ends at Subject Exit. 
In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB), the site investigator will report SAEs to the IRB   within timeframe 
required.  Please notify Grace Medical within 5 working days. 
 
11.4  Unanticipated Adverse Device Effects 
 
If an SAE is also an unanticipated adverse device effect, the investigator must submit to 
Grace Medical (within 3 business days) and reviewing IRB a report but within 10 working 
days. 
 
12 
DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
12.1 Early Discontinuation  
A subject may be discontinued from study treatment at any time if the subject, the 
investigator, or the Sponsor feels that it is not in the subject’s best interest to continue.  The 
following is a partial list of possible reasons for study treatment discontinuation:  
1.  Subject withdrawal of consent (or assent) 
2.  Lost to or refused follow-up 
3.  Adverse Event or Serious Adverse Event if investigator feels that it is in the best interest 
of the patient. 
If a subject is withdrawn from treatment due to an adverse event, the subject will be 
followed and treated by the Investigator until the abnormal parameter or symptom has 
resolved or stabilized.   
All subjects who discontinue study treatment should come in for an early discontinuation 
visit as soon as possible and then should be encouraged to complete all applicable 
remaining scheduled visits and procedures. 
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in the 
subject’s source documents. 
 

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12.2  Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject, the investigator, or the 
sponsor feels that it is not in the subject’s best interest to continue.   
The reason for the subject’s withdrawal from the study will be specified in the subject’s 
source documents as well as Study Exit Form 
 
12.3  Replacement of Subjects 
Subjects who withdraw from the study may be replaced up to a total of 15 for the site.   
 
13 
 PROTOCOL DEVIATIONS 
A protocol deviation occurs when the subject, investigator, or Sponsor fails to adhere to 
significant protocol requirements affecting the inclusion, exclusion, subject safety and 
primary endpoint criteria.  Protocol deviations for this study include, but are not limited to, 
the following: 
1.  Failure to Obtain Informed Consent 
2.  Failure to meet inclusion/exclusion criteria (Eligibility) 
3.  Failure to maintain study evaluation time frames for follow-up visits  
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol 
deviation.  The Sponsor will determine if a protocol deviation will result in withdrawal of a 
subject. 
When a protocol deviation occurs, it will be discussed with the investigator and a Protocol 
Deviation Form detailing the deviation will be completed.  This form will be signed by a 
Sponsor representative and the Investigator.  A copy of the form will be filed in the site’s 
regulatory binder and in the Sponsor’s files.   
Protocol deviations should also be reported as required to the site’s IRB. 
 
14 
STATISTICAL METHODS AND CONSIDERATIONS  
 
As this study is for safety and utilizing a small number of subjects, no statistical analysis will 
be completed.  Information will be presented to the FDA in tabular format. 
 
Adverse event rates will be coded by body system will include the number of patients for 
whom the event occurred, the rate of occurrence, and the severity and relationship to study 
device.   
14.1 Sample Size and Randomization 
Up to 30 subjects will be enrolled in this non-randomized study.  The number of subjects 
was determined by discussion with the FDA. 
 

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15 
DATA COLLECTION, RETENTION AND MONITORING 
15.1 Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents 
designed to record all observations and other pertinent data for each subject treated with the 
study device.   
 
Study personnel at each site will enter data from source documents corresponding to a 
subject’s visit into the Case Report Forms (CRFs) provided when the information 
corresponding to that visit is available.  Subjects will not be identified by name in the study 
database or on any study documents to be collected by the Sponsor (or designee), but will 
be identified by subject number and initials. 
 
If any correction is made on a CRF, the study staff member will line through the incorrect 
data, write in the correct data and initial and date the change. 
 
The Investigator is responsible for all information collected on subjects enrolled in this 
study.  All data collected during the course of this study must be reviewed and verified for 
completeness and accuracy by the Investigator.  Copies of the completed CRFs will remain 
at the Investigator’s site at the completion of the study. 
15.2 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB, and Regulatory Agency (e.g., FDA) 
inspectors upon request.  A file for each subject must be maintained that includes the 
signed Informed Consent, HIPAA Authorization and Assent Form and copies of all source 
documentation related to that subject.  The Investigator must ensure the reliability and 
availability of source documents from which the information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, Study 
File Notebook, etc.) must be kept secured for a period of two years following marketing of 
the investigational product or for two years after centers have been notified that the study 
has been discontinued.  There may be other circumstances for which the Sponsor is 
required to maintain study records and, therefore, the Sponsor should be contacted prior to 
removing study records for any reason. 
15.3 Monitoring 
Grace Medical, Inc. will serve as the sponsor of this investigational clinical study. It is the 
responsibility of the sponsor of this clinical study to ensure proper monitoring to see that the 
study is conducted in full compliance with the study protocol in conformance to Title 21, 
Code of Federal Regulations (CFR) Parts, 50, 54, 56, and 812, Guidelines for the 
Monitoring of Clinical Investigations and the Declaration of Helsinki, as amended.  The 
study will be monitored by a Clinical Research Associate or designee of Grace Medical 
(Clinical Monitor). 
 
By signing this protocol, the Investigator grants permission to the Sponsor (or designee), 
and appropriate regulatory authorities to conduct on-site monitoring and/or auditing of all 
appropriate study documentation. 
 
 

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15.3.1 
SITE INITIATION VISIT 
Once all regulatory documents and approval are received, a site initiation visit will be 
scheduled.  During this visit, the Monitor will review the following with the Principal 
Investigator and his/her staff as appropriate: 
1. Study goals and obligations 
2. Protocol procedures (with particular attention to inclusion/exclusion criteria, 
enrollment goals, adverse events, primary efficacy variables and GCP compliance) 
3. Informed consent procedure 
4. AE/SAE reporting 
5. CRF completion and error correction/need for adequate source documentation 
6. Maintenance of the investigator binder and site visit log 
7. Investigational status of test article and requirements for accountability 
8. Any other issue as deemed important to the conduct of the study 
 
At this time, the following documents will be obtained if not already forwarded to Grace 
Medical: 
1. Copy of IRB/EC approval letter 
2. Copy of IRB/EC approved informed consent document 
3. Signed Clinical Trial Research Agreement 
4. Curricula vitae and Medical Licenses for the Principal Investigator and each Sub-
Investigator 
5. Financial Disclosure Form 
 
15.3.2 INTERIM MONITORING VISITS 
The first interim monitoring visit at each site will be made after the majority of subjects have 
completed the four week follow-up visit unless it is determined that a visit should be made 
earlier.  The Clinical Research Associate or designee will maintain personal contact with the 
Investigator(s) and study personnel by telephone, mail, email and on-site visits.  The 
Clinical Research Associate or designee will require access to all subject and study records 
in order to verify that: 
 
1. Informed consent has been obtained for each subject 
2. The site is in compliance with the study protocol 
3. Source documentation and CRF completion 
4. Study administration records are complete 
5. Product inventory is verified and accurate 
 
The Study Site Documentation Binder will also be reviewed.  Additional monitoring visits will 
be scheduled as appropriate.  
 
15.3.3 
FINAL MONITORING VISIT 
At the close of the study, the Clinical Research Associates or designee will conduct a final 
visit to conduct the following: 
 
1. Collect outstanding data  
2. Insure the completeness of study files  
3. Review record retention requirements with study personnel  
4. Provide for disposition of any remaining study supplies and devices. 

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15.3.4 
STUDY SITE DOCUMENTATION BINDER 
The Study Coordinator at each site will be trained on the proper maintenance of the Study 
Site Documentation Binder (Regulatory Binder). Correspondence, agreements, and logs are 
to be kept up–to date and copies should be forwarded to the Sponsor in a timely fashion.  
 
The contents of the Study Site Documentation Binder may include but are not limited to: 
 
1.  Clinical Trial Research Agreement / contract  
2.  Financial Disclosure Forms 
3.  IRB Approval & Correspondence 
4.  IRB Approved Consent Form 
5.  Investigator CVs (signed & dated) 
6.  Training / Meeting Log 
7.  Signature Log 
8.  Device Log 
9.  Screening Log 
10. Patient Enrollment Log 
11. Sponsor Monitoring Log 
12. Study Communication 
15.4 
Subject Confidentiality 
In order to maintain subject confidentiality, only a subject number and subject initials will 
identify all study subjects on CRFs and other documentation submitted to the Sponsor.   
16 
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of Human 
Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of 
Clinical Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number and initials only.  All study records will be kept 
in a locked file cabinet and code sheets linking a patient’s name to a patient identification 
number will be stored separately in another locked file cabinet.  Clinical information will not 
be released without written permission of the subject, except as necessary for monitoring by 
the FDA.  The Investigator must also comply with all applicable privacy regulations (e.g., 
Health Insurance Portability and Accountability Act of 1996, EU Data Protection Directive 
95/46/EC). 
16.1 
Protocol Amendments 
Any amendment to the protocol will be written by the Sponsor.  Protocol amendments 
cannot be implemented without prior written IRB approval except as necessary to eliminate 
immediate safety hazards to patients.  A protocol amendment intended to eliminate an 
apparent immediate hazard to patients may be implemented immediately, provided the 
IRBs are notified within five working days. 
 

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16.2 
Institutional Review Boards  
The protocol and consent form will be reviewed and approved by the IRB of each 
participating center prior to study initiation.  Serious adverse events regardless of causality 
will be reported to the IRB in accordance with the standard operating procedures and 
policies of the IRB, and the Investigator will keep the IRB informed as to the progress of the 
study.  The Investigator will obtain assurance of IRB compliance with regulations. 
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, protocol 
amendments, consent forms, information concerning patient recruitment, payment or 
compensation procedures, or other pertinent information) will be submitted to the IRB.  The 
IRB’s written unconditional approval of the study protocol and the informed consent form will 
be in the possession of the Investigator before the study is initiated.  The IRB’s 
unconditional approval statement will be transmitted by the Investigator to the Sponsor or 
designee prior to the shipment of study supplies to the site.  This approval must refer to the 
study by exact protocol title and number and should identify the documents reviewed and 
the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without 
prior written IRB approval except when necessary to eliminate immediate hazards to the 
patients or when the change(s) involves only logistical or administrative aspects of the 
study.  Such modifications will be submitted to the IRB and written verification that the 
modification was submitted and subsequently approved should be obtained.   
The IRB must be informed of revisions to other documents originally submitted for review; 
serious and/or unexpected adverse experiences occurring during the study in accordance 
with the standard operating procedures and policies of the IRB; new information that may 
affect adversely the safety of the patients of the conduct of the study; an annual update 
and/or request for re-approval; and when the study has been completed. 
16.3 
Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, 
US Code of Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], 
CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and 
Accountability Act (HIPAA, if applicable), and local regulations. 
The Investigator will prepare the informed consent form, assent and HIPAA authorization 
and provide the documents to the Sponsor or designee for approval prior to submission to 
the IRB.  The consent form generated by the Investigator must be acceptable to the 
Sponsor and be approved by the IRB.  The written consent document will embody the 
elements of informed consent as described in the CFR 50.25. The Investigator will send an 
IRB -approved copy of the Informed Consent Form to the Sponsor (or designee) for the 
study file. 
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial.  Information should be given in both oral and written form 
and subjects (or their legal guardian) must be given ample opportunity to inquire about 
details of the study.  If appropriate and required by the local IRB, assent from the subject 
will also be obtained.  If a subject is unable to sign the informed consent form (ICF) and the 
HIPAA authorization, a legal guardian may sign for the subject.   A copy of the signed 
consent form (and assent) will be given to the subject or legal guardian of the subject and 
the original will be maintained with the subject’s records. 

Protocol 2015.01 - Rev. B Tympanoseal Research Protocol, Grace Medical, Inc. Confidential 
 
Version Date: 07/12/2017  
 
Page 29 of 30 
 
16.4 
Publications  
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual written agreement among the 
study Sponsor and participating institutions.  The publication or presentation of any study 
results shall comply with all applicable privacy laws, including, but not limited to, the Health 
Insurance Portability and Accountability Act of 1996.  
16.5 
Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1.  Conduct the study in accordance with the protocol and only make changes after notifying 
the Sponsor (or designee), except when to protect the safety, rights or welfare of subjects. 
2.  Personally conduct or supervise the study (or investigation). 
3.  Ensure that the requirements relating to obtaining informed consent and IRB review and 
approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4.  Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 812 
5.  Ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments. 
6.  Maintain adequate and accurate records in accordance with §21 CFR 812 and to make 
those records available for inspection with the Sponsor (or designee). 
7.  Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8.  Promptly report to the IRB and the Sponsor (or designee) all changes in the research 
activity and all unanticipated problems involving risks to subjects.  
9.  Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators and 
all other pertinent requirements listed in § 21 CFR 812. 
 

Protocol 2015.01 – Rev. B Tympanoseal Research Protocol, Grace Medical, Inc. Confidential 
 
Version Date:  07/12/2017 
 
Page 30 of 30 
 
APPENDIX 1    SCHEDULE OF STUDY VISITS 
 
 
 
 
Enrollment* 
 
Procedure* 
 
Same Day 
Enrollment & 
Procedure 
 
4  Weeks 
(+ 7 days)  
 
10  Weeks 
(+ 7 days)  
 
16  Weeks 
(+ 14 days) 
 
Add’l Visit(s) 
20 weeks, 24 
weeks, 30 weeks 
36 weeks  
(+ 14 days) 
Informed Consent 
X 
 
X 
 
 
 
 
Inclusion / Exclusion 
X 
 
X 
 
 
 
 
Medical /ENT History 
X 
 
X 
 
 
 
 
Physical Exam 
X* 
X* 
X 
X 
X 
X 
X 
Vital Signs 
X* 
X* 
X 
X 
X 
X 
X 
Study Visit Evaluation 
X* 
X* 
X 
X*** 
X*** 
X*** 
X*** 
Otomicroscopy with 
Photograph 
X** 
X** 
PRE &  
POST 
X 
X 
X 
X 
Use of Study Device 
 
X 
X 
 
 
 
 
Concomitant 
Medication 
X* 
X* 
X 
X 
X 
X 
X 
Adverse Event**** 
 
X 
X 
X 
X 
X 
X 
Subject Study Exit 
 
 
 
X*** 
X*** 
X*** 
X*** 
 
 
*Enrollment and Procedure may be the same visit and duplicate CRFs do not need to be completed.  Informed Consent must be 
signed prior to any study procedures. 
**  Otomicroscopy with Photograph is required Pre and Post Procedure. 
*** If healing is noted by investigator, the subject may exit the study. 
**** If applicable