A Prospective Post-Market Clinical Evaluation of Miromatrix Biological Mesh for Hiatal Hernia Repair
Phase: NA
Conditions: Hiatal Hernia
Sponsor: Miromatrix Medical Inc.

 
 
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A Prospective Post-Market Clinical Evaluation of Miromatrix Biological Mesh for 
Hiatal Hernia Repair  
(MIROMESH PM-2) 
 
Protocol Number 2015002 
 
Version B 
June 5, 2015 
 
Miromatrix Medical Inc. 
10399 West 70th Street 
Eden Prairie, MN 55344 
 
 
 
 
 
 
 
Approvals 
Name and Title 
Signature 
Date 
Robert Cohen, President & CEO 
 
 
Jeff Ross, Ph.D., VP of Product 
Development 
 
 
Angela Sullivan, Clinical Trials Manager 
 
 
 
 
 
 
 
 
 
 

 
 
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MIROMATRIX MEDICAL 
Clinical Research Protocol 
 
A PROSPECTIVE POST-MARKET CLINICAL EVALUATION OF MIROMATRIX 
BIOLOGICAL MESH FOR HIATAL HERNIA REPAIR (“MIROMESH PM-2”) 
Protocol Number: 
2015002 
Version Date: 
June 5, 2015 
Device: 
Miromatrix Biologic Mesh (MIROMESH®) 
Study Phase: 
Post Market 
Sponsor: 
Miromatrix Medical Inc. 
10399 West 70th Street 
Eden Prairie, MN 55344 
National Principal 
Investigator: 
Michael Rosen, MD 
 
 
 

 
 
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TABLE OF CONTENTS 
 
1.0 
PURPOSE OF THE INVESTIGATION .................................................. 10 
1.1. Background ......................................................................................... 10 
1.2. Name of study device.......................................................................... 11 
1.3. Description of study device ................................................................ 11 
1.4. Intended use of the study device ....................................................... 11 
1.5. Objectives of the clinical investigation ............................................. 11 
1.5.1. 
Primary objective ............................................................................................................... 11 
1.5.2. 
Secondary objective(s) ..................................................................................................... 11 
1.6. Anticipated duration of the clinical investigation ............................. 11 
2.0 
CLINICAL PROTOCOL ........................................................................ 11 
2.1 
Protocol number and title ................................................................... 11 
2.2 
Protocol version number and date .................................................... 11 
2.3 
Study design ........................................................................................ 11 
2.4 
Subject selection ................................................................................. 12 
2.4.1 
General characteristics of the proposed subject population(s) .................................... 12 
2.4.2 
Anticipated number of research subjects ....................................................................... 12 
2.4.3 
Inclusion criteria ................................................................................................................ 12 
2.4.4  
Exclusion criteria ............................................................................................................... 12 
2.5 
Study procedures ................................................................................ 13 
2.5.1 
Screening and consenting procedures ........................................................................... 13 
2.5.2 
Surgical treatment ............................................................................................................. 13 
2.5.3 
Study visits ........................................................................................................................ 14 
2.5.5 
Withdrawal of subjects due to non-compliance ............................................................. 16 
2.5.6 
Procedures to assess efficacy ......................................................................................... 17 
2.5.7 
Procedures to assess safety ............................................................................................ 17 
2.6 
Study outcome evaluations ................................................................ 17 
2.6.1 
Study endpoints ................................................................................................................ 17 
2.6.2 
Sample size determination ............................................................................................... 17 
2.6.3 
Outcome data and data analysis ...................................................................................... 18 
2.6.4 
Data and Safety Monitoring Committee ........................................................................... 19 
3.0 
RISK ANALYSIS ................................................................................... 19 
3.2 
Adverse event reporting ..................................................................... 19 
3.2.1 
Adverse event definitions ................................................................................................. 19 
3.2.2  
Eliciting adverse effect information ................................................................................. 20 
3.2.3  
Recording and assessment of adverse effects ............................................................... 20 
3.2.4 
Causality and severity assessment ................................................................................. 20 

 
 
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3.2.5 
Reporting MDR reportable events to the FDA ................................................................. 20 
3.2.6 
Reporting adverse effects to the responsible IRB .......................................................... 21 
3.3 
Withdrawal of subjects due to adverse effects ................................. 21 
4.0 
MONITORING PROCEDURES ............................................................. 21 
5.0 
LABELING ............................................................................................ 21 
6.0 
INFORMED CONSENT ......................................................................... 21 
7.0 
IRB INFORMATION .............................................................................. 22 
8.0 
ADDITIONAL RECORDS AND REPORTS .......................................... 22 
8.1 
Data handling and record-keeping..................................................... 22 
8.2 
Record maintenance and retention.................................................... 23 
9.0 
PUBLICATIONS ................................................................................... 24 
9.1 
Authorship ........................................................................................... 24 
9.2 
Trial Registration ................................................................................. 24 
References ........................................................................................................ 25 
APPENDIX A ...................................................................................................... 26 
APPENDIX B ...................................................................................................... 27 
APPENDIX C ...................................................................................................... 28 
 
 
 
 

 
 
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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ASA 
American Society of Anesthesiology 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
EGD 
Esophagogastroduodenoscopy 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GEJ 
Gastroesophageal Junction 
GERD-HRQL 
Gastroesophageal Reflux Disease Health-Related Quality-Of-Life 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
MDR 
Medical Device Reporting 
PI 
Principal Investigator 
QC 
Quality Control 
QOL 
Quality of Life 
SF-36®  
The Short-Form (36) Health Survey 
SF-36v2™ 
The newest version of the SF-36 
Survey Materials 
SF-36 Licensed Surveys, Software, SMS Scoring Solution, and all 
intellectual property rights related thereto 
UGI 
Upper Gastrointestinal Imaging 
 
 

 
 
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PROTOCOL SYNOPSIS 
TITLE 
A Prospective Post-Market Clinical Evaluation of Miromatrix 
Biological Mesh for Hiatal Hernia Repair  
SHORT TITLE 
MIROMESH PM-2 
SPONSOR 
Miromatrix Medical Inc. 
NUMBER OF SITES 
Up to 6 
RATIONALE 
This study is being conducted to gather long-term data of the 
performance of the Miromatrix Biological Mesh.  
STUDY DESIGN 
This is a post-market, interventional, prospective, single arm, multi-
site study.   
PRIMARY OBJECTIVE 
The primary objective is to summarize freedom from hernia 
recurrence requiring reoperation at two years post procedure.   
SECONDARY 
OBJECTIVES 
The secondary objectives are to: 
• 
Summarize freedom from hernia recurrence requiring 
reoperation at one year post procedure 
• 
Summarize quality of life and freedom from symptomatic 
hernia recurrence over time 
• 
Summarize freedom from hernia recurrence as seen on 
radiographic imaging over time 
• 
Summarize device-related and procedure-related adverse 
events over time 
• 
Summarize procedure characteristics for the hiatal hernia 
repair surgery 
PRIMARY ENDPOINT 
The primary endpoint is an assessment of hernia recurrence requiring 
surgical reoperation at two years year post procedure for subjects that 
received implant of the mesh.   
SECONDARY ENDPOINTS 
• 
Assessment of hernia recurrence requiring surgical 
reoperation at one year post procedure for subjects that 
received implant of the mesh 
• 
Assessment of quality of life and symptomatic hernia 
recurrence using the SF-36, GERD-HRQL, and symptom 
questionnaires at baseline, 2 weeks, 2 months, 6 months, 1 
year, 18 months, and 2 years 
• 
Assessment of hernia recurrence >2 cm as seen on 
radiographic imaging at one year and two years post 
procedure in comparison to discharge imaging.  
• 
Assessment of device-related and procedure-related adverse 
events over time 
• 
Procedure characteristics for the hiatal hernia repair surgery 
will include at a minimum: 
− 
Length of hospital stay 
− 
Procedure time 
− Implant success 
NUMBER OF SUBJECTS 
Up to 50 subjects will be enrolled in this study.   

 
 
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INCLUSION CRITERIA 
To be considered for study participation, prospective subjects must: 
• 
be between 18 and 80 years old on the day of study 
enrollment 
• 
be able and willing to sign the consent form and comply with 
all study visits and procedures 
• 
be able to undergo elective laparoscopic hiatal hernia repair 
• 
be free of cognitive or speech impairment 
• 
have a documented, symptomatic type II or III hernia ≥5cm 
in the axial/vertical dimension 
• 
commit to non-smoking for at least 4 weeks prior to 
procedure 
EXCLUSION CRITERIA 
To be considered for study participation, prospective subjects must 
NOT: 
• 
have had a previous operation of the esophagus or stomach 
• 
have a sensitivity to porcine material 
• 
be pregnant or plan to be pregnant within next 2 years 
• 
be immunocompromised or at risk of 
immunosuppression (i.e. be HIV positive, be experiencing 
organ rejection, be a recent or anticipated chemotherapy 
recipient) as determined by the Investigator 
• 
require emergent operation for acute gastric volvulus or 
strangulation 
• 
be American Society of Anesthesiology (ASA) class 4 or 
greater 
• 
have a BMI ≥40 
• 
have a life expectancy of less than 2 years at the time of 
enrollment 
• 
have an associated gastrointestinal disease that requires 
extensive medical or surgical intervention that might 
interfere with the quality of life assessment (e.g. Crohn’s 
disease) 
• 
have any condition in the opinion of the Investigator that 
would preclude the use of the study device, or preclude the 
subject from completing the follow-up requirements 
INTENDED USE OF 
STUDY DEVICE 
The Miromatrix Biologic Mesh is intended to be implanted to 
reinforce soft tissue. 
DURATION OF SUBJECT 
PARTICIPATION AND 
DURATION OF STUDY 
Subjects will be enrolled in the study for up to 2 years (± 30 days) 
Screening:  up to 60 days 
Treatment: 1 day (surgical procedure) 
Follow-up:  Discharge, 2 week, 2 month, 6 month, 1 year, 18 
month, and 2 year 
EVALUATIONS 
X-ray series with barium swallow (UGI) 
SF-36 Quality of Life (QOL) Survey 
GERD-HRQL Questionnaire 
Symptom Visual Analog Scales (VAS) 

 
 
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STATISTICS 
Primary Analysis Plan 
This trial is descriptive in nature with no pre-specified hypothesis.  
Continuous data will be summarized using means, standard 
deviations, medians, ranges, and possibly 95% confidence intervals.  
In addition, where assessments are made over time, the differences 
from baseline may be statistically tested to see if different from zero 
using paired Student’s t-test for parametric data or Wilcoxon Signed 
Rank test if non-parametric data.  An alpha of 0.05 will be considered 
statistically significant and no adjustments for multiple testing will be 
made.  Categorical data will be presented as counts and percentages. 
Rationale for Number of 
Subjects 
Up to 50 subjects will be enrolled to provide data of hernia 
recurrence at two years post procedure in addition to long-term 
symptomatic and asymptomatic hernia recurrence and quality of life.  
There is not a pre-specified sample size calculation, but a sample size 
of 30 is “rule of thumb” generally accepted as an adequate sample 
size for human studies. (1) 
 
 
 
 

 
 
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1.0 
PURPOSE OF THE INVESTIGATION 
1.1. 
Background 
Surgical mesh used for hernia repair is classified by the FDA as a Class II medical device, which 
means that new surgical meshes receive “clearance” for marketing via the 510(k) process.  In 
order for a new surgical mesh to receive clearance, it is required to demonstrate substantial 
equivalence to a predicate device.  The process is designed to assure safety and efficacy of new 
Class II devices without requiring over-burdensome clinical data.  It fosters the advancement of 
technology and allows new manufacturers to enter the marketplace in an expeditious fashion 
without introducing unreasonable risk to the public.  Because clinical data is not required for a 
company to receive 510(k) clearance of a device, and because clinical trials can be extremely 
costly, there is a scarcity of prospective safety and efficacy-driven trials for new surgical meshes.  
The relative lack of clinical data for the many types of surgical mesh on the market today can 
make it difficult for surgeons to select the best mesh for a given procedure.  
 
Hiatal hernia repair may be done with or without the use of mesh; however, the SAGES 
Guidelines Committee states that “the use of mesh reinforcement of large hiatal hernia repairs 
leads to decreased short term recurrence rates” (2).  The Committee also identifies a need for 
longer-term results.  Extending the focus from large hiatal hernias to small ones, Schmidt et al. 
performed a retrospective review of 70 patients with 1-5 cm hiatal hernias and reported a 
recurrence rate of 16% (5/32) in the suture cruroplasty group, compared with a recurrence rate of 
0% (0/38) in the group with crural reinforcement with absorbable mesh (3).  Their research 
points to the value of using biologic mesh in even small hiatal hernia repairs.   
Despite ongoing concerns related to the use of synthetic mesh in hiatal hernia repair including 
erosion, dysphagia, and stricture, Wassenaar et.al. studied 73 subjects who had laparoscopic 
hiatal hernia repair with biologic mesh, with a median follow-up time of 45 months totaling 530 
patient years, and found no evidence of stricture, ulceration, or erosion in any of the patients.  
Given the absence of major complications and the high (>90%) overall satisfaction with the 
operation, this research underscores the value of biologic mesh for hiatal hernia repair (4).   
Miromatrix Medical has developed MIROMESH® - a new, noncrosslinked, acellular mesh 
derived from the highly vascularized porcine liver.  MIROMESH received FDA 510(k) 
clearance with an indication for reinforcement of soft tissue on March 31, 2014 under K134033.  
The company believes that this biological mesh is superior to other biological meshes on the 
market due to the unique sourcing and processing of the material.  The perfusion 
decellularization technique used to create the product is the only technology available to fully 
decellularize solid organs while maintaining their structure and vasculature, thereby allowing 
production of a highly vascularized, full-thickness biological mesh for hernia repair. The 
substantial vascularity and favorable tissue composition of this biological mesh differentiate it 
from the thin, dense (primarily skin) tissues currently on the market that rely on immersion 
decellularization.  
This study will serve to provide clinicians with high-quality clinical data in order to provide 
them with a higher degree of confidence when selecting MIROMESH for hiatal hernia repair.   

 
 
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1.2. 
Name of study device 
The study device is Miromatrix Biological Mesh (MIROMESH®). 
1.3. 
Description of study device 
Miromatrix Biologic Mesh is an FDA-cleared medical device.  It is a noncrosslinked acellular 
surgical mesh that is derived from the highly vascularized porcine liver and is processed and 
stored in a phosphate buffered aqueous solution.  Miromatrix Biologic Mesh is packaged in an 
inner sterile pouch and outer non-sterile pouch.   
1.4. 
Intended use of the study device 
The Miromatrix Biological Mesh is intended to be implanted to reinforce soft tissue. 
 
1.5. 
Objectives of the clinical investigation 
1.5.1. Primary objective 
The primary objective is to summarize freedom from hernia recurrence requiring operation at 
two years post procedure. 
1.5.2. Secondary objective(s) 
The secondary objectives are to: 
• Summarize freedom from hernia recurrence requiring reoperation at one year post 
procedure 
• Summarize quality of life and freedom from symptomatic hernia recurrence over time 
• Summarize freedom from hernia recurrence as seen on radiographic imaging over time 
• Summarize device-related and procedure-related adverse events over time 
• Summarize procedure characteristics for the hiatal hernia repair surgery 
1.6. 
Anticipated duration of the clinical investigation 
The anticipated duration of the clinical duration is 30 months.  This duration covers enrollment 
of the first study subject to 2-year follow-up of the last study subject. 
2.0 
CLINICAL PROTOCOL 
2.1 
Protocol number and title  
2015002: A Prospective Post-Market Clinical Evaluation of Miromatrix Biological Mesh for 
Hiatal Hernia Repair (MIROMESH PM-2) 
2.2 
Protocol version number and date  
Version B, June 5, 2015 
2.3 
Study design 
This is a post-market, interventional, prospective, single arm, multi-site study.   

 
 
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2.4 
Subject selection 
2.4.1 General characteristics of the proposed subject population(s) 
The proposed subject population includes males and females between 18 and 80 years of age 
who are candidates for repair of a hiatal hernia with surgical mesh.   
2.4.2 Anticipated number of research subjects 
Up to 50 subjects will be enrolled in the study.  Enrollment is defined as the point at which the 
prospective subject signs the IRB-approved consent form, however only subjects that are 
enrolled AND have an implant attempted will count toward the sample size.  A sample size of 30 
is “rule of thumb” generally accepted as an adequate sample size for preliminary summaries.  
Assuming 100% implant success and a 10% 2-year attrition rate, at least 27 subjects are expected 
to complete the study.  
2.4.3 Inclusion criteria 
To be considered for study participation, prospective subjects must: 
• 
be between 18 and 80 years old on the day of study enrollment 
• 
be able and willing to sign the consent form and comply with all study visits and procedures 
• 
be able to undergo elective laparoscopic hiatal hernia repair 
• 
be free of cognitive or speech impairment 
• 
have a documented, symptomatic type II or III hernia ≥5cm in the axial/vertical dimension 
• 
commit to non-smoking for at least 4 weeks prior to procedure 
2.4.4  Exclusion criteria 
To be considered for study participation, prospective subjects must NOT: 
• 
have had a previous operation of the esophagus or stomach 
• 
have a sensitivity to porcine material 
• 
be pregnant or plan to be pregnant within next 2 years 
• 
be immunocompromised or at risk of immunosuppression (i.e. be HIV positive, be experiencing 
organ rejection, be a recent or anticipated chemotherapy recipient) as determined by the 
Investigator 
• 
require emergent operation for acute gastric volvulus or strangulation 
• 
be American Society of Anesthesiology (ASA) class 4 or greater 
• 
have a BMI ≥40 
• 
have a life expectancy of less than 2 years at the time of enrollment 
• 
have an associated gastrointestinal disease that requires extensive medical or surgical intervention 
that might interfere with the quality of life assessment (e.g. Crohn’s disease) 
• 
have any condition in the opinion of the Investigator that would preclude the use of the study 
device, or preclude the subject from completing the follow-up requirements 
 

 
 
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2.5 
Study procedures 
2.5.1 Screening and consenting procedures 
Patients who are candidates for laparoscopic hiatal hernia repair will be considered for study 
participation.  Trained site personnel will review prospective study subject charts to rule out any 
obvious study exclusion criteria prior to introducing the study to the patient.   
 
Prior to the hernia repair surgery, the Principal Investigator (or a trained and qualified delegate) 
will introduce the study and review the full set of study criteria with the patient.  If the patient 
meets all study criteria, the PI or delegate will review the current IRB-approved consent form 
with the patient.  The patient will be encouraged to ask questions and will have all of their 
questions addressed to their satisfaction before deciding whether or not to be in the study.  A 
copy of the consent form will be made available to the subject to take home for review and 
discussion with family members.  If the patient agrees to participate in the study, (s)he will sign 
the consent form and will be provided with a signed copy for their records.  Upon signing the 
consent form, the patient will be considered “enrolled” as a study subject.  Refer to section 6.0 
for additional details about the consent process. 
2.5.2 Surgical treatment  
Antibiotics will be administered prophylactically according to the physician’s standard practice.   
 
All study subjects will receive the FDA cleared MIROMESH study device as part of their 
laparoscopic hiatal hernia repair surgery.  Prior to use, the study device(s) will be soaked for a 
minimum of 2 minutes using a sterile basin and room temperature sterile saline or room 
temperature sterile lactated Ringer’s solution to cover the mesh.   
The hernia sac should be dissected away from mediastinal structures and excised whenever 
possible.  The gastroesophageal junction (GEJ) will be returned to a tension-free 
infradiaphragmatic position with the intra-abdominal esophagus measuring at least 2 cm.  Collis 
gastroplasty, as well as gastropexy, will be documented for study records if performed.   
The crura will be closed with interrupted sutures whenever possible.  MIROMESH should be 
trimmed in a way to accommodate the specific subject’s anatomy and defect, and should then be 
placed in an onlay fashion to reinforce primary crural closure.  A small space of at least 0.5 cm 
should be left between the edge of the mesh and the esophageal wall to avoid excessive contact 
of the mesh with the esophagus (4) (5).  Mesh fixation may be achieved with glue, tacks, or 
sutures, or any combination thereof.  Care should be taken that fixation methods do not breach 
the aorta or pericardium when applied low on the left crus or near the apex of the crura anteriorly 
(2).  Fundoplication will be performed at the discretion of the investigator and the degree of wrap 
will be documented for study records.   
Subjects should not be placed on the immunosuppressant drug rapamycin for at least 30 days 
post-surgery, as it has been shown to inhibit vascularization and incorporation of surgical mesh 
(6). 

 
 
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2.5.3 Study visits 
 
Table 1. Schedule of Study Visit Activities 
 
Activity 
Study Visit 
Enrollment 
Baseline 
(within 60 days 
of Procedure) 
Procedure 
Discharge 
(may be 1 
day prior) 
Follow-Up Time Period from Surgery 
2 Week 
( ±7 days)  
2 Month 
(± 15 days) 
6 Month* 
(± 30 days) 
1 Year 
(± 30 days) 
18 Month* 
(± 30 days) 
2 Year 
(± 30 days) 
Review study 
criteria 
X 
 
 
 
 
 
 
 
 
 
Medical History  
 
X 
 
 
 
 
 
 
 
 
Physical Exam  
 
X 
 
X 
X 
X 
 
X 
 
X 
SF-36 QOL 
Survey 
 
X 
 
 
X 
X 
X 
X 
X 
X 
GERD-HRQL 
and Symptoms 
Survey 
 
X 
 
 
X 
X 
X 
X 
X 
X 
UGI X-ray with 
barium 
 
 
 
X 
 
 
 
X 
 
X 
Assess Adverse 
Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
* The 6-Month and 18-Month Visits may be conducted remotely via telephone, email, and/or mail. 
 
Table 2. Schedule of Study Visit Case Report Forms 
 
CRF Name 
Study Visit 
Enrollment 
Baseline 
(within 60 days 
of Procedure) 
Procedure 
Discharge 
(may be 1 
day prior) 
Follow-Up Time Period from Surgery 
2 Week  
( ±7 days)  
2 Month 
(± 15 days) 
6 Month* 
(± 30 days) 
1 Year 
(± 30 days) 
18 Month* 
(± 30 days) 
2 Year 
(± 30 days) 
Enrollment 
X 
 
 
 
 
 
 
 
 
 
Baseline  
 
X 
 
 
 
 
 
 
 
 
Procedure 
 
 
X 
 
 
 
 
 
 
 
Follow-Up 
 
 
 
X 
X 
X 
 
X 
 
X 
SF-36  
 
X 
 
 
X 
X 
X 
X 
X 
X 
Symptoms** 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Protocol Deviation 
As Applicable 
Adverse Event 
As Applicable 
Re-intervention 
As Applicable 
Discontinuation 
As Applicable (must complete one per subject) 
* The 6-Month and 18-Month Visits may be conducted remotely via telephone, email, and/or mail. 
**The Symptoms CRF includes the GERD-HRQL survey as well as symptom Visual Analog Scales

 
 
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At the Enrollment Visit, study inclusion and exclusion criteria will be reviewed.  If the patient 
meets all inclusion criteria and none of the exclusion criteria and wishes to participate in the 
study after careful consideration, they will be asked to sign the consent form.  The patient is 
considered to be enrolled as a study subject upon signing the consent form. 
 
At the Baseline Visit, the subject’s demographics, medical history, and hernia information will 
be reviewed and recorded on the Baseline CRF.  The subject will be asked to complete the SF-36 
QOL and Symptoms CRF.  This visit should be conducted within sixty (60) days prior to the 
procedure. 
 
At the Procedure Visit, the subject will be undergo laparoscopic hiatal hernia repair according 
to section 2.5.2 above.  Procedural details to be collected on the Procedure CRF include: surgery 
duration, operative approach and technique, hernia sac dissection and excision, mesh trimming 
and placement, fundoplication degree, gastropexy, gastroplasty, fixation information, hernia size, 
device size and lot number. 
 
At the Discharge Visit, physical exam information will be recorded on the Follow-Up CRF and 
the subject will have a UGI x-ray with barium contrast.  The discharge visit may be conducted 1 
day prior to discharge. 
 
At the 2-Week Visit and 2-Month Visit, physical exam information will be recorded on the 
Follow-Up CRF.  The subject will be asked to complete the SF-36 QOL and Symptoms CRF.  
The 2-week visit allows for a ±7 day window.  The 2-month visit allows for a ±15 day window. 
 
The 6-Month Visit may be conducted remotely via telephone, email, and/or mail.  The subject 
will be asked to complete the SF-36 QOL and Symptoms CRF, both which should be 
administered in a manner that is convenient to the subject.  The subject should also be asked 
specifically about reportable adverse events.  The 6-month visit allows for a ±30 day window. 
 
At the 1-Year Visit, physical exam information will be recorded on the Follow-Up CRF and the 
subject will have a UGI x-ray with barium contrast.  The subject will be asked to complete the 
SF-36 QOL and Symptoms CRF.  The 1-Year visit allows for a ±30-day window. 
 
The 18-Month Visit may be conducted remotely via telephone, email, and/or mail.  The subject 
will be asked to complete the SF-36 QOL and Symptoms CRF, both which should be 
administered in a manner that is convenient to the subject.  The subject should also be asked 
specifically about reportable adverse events.  The 18-month visit allows for a ±30 day window. 
 
At the 2-Year Visit, physical exam information will be recorded on the Follow-Up CRF and the 
subject will have a UGI x-ray with barium contrast.  The subject will be asked to complete the 
SF-36 QOL and Symptoms CRF.  The 2-Year visit allows for a ±30-day window. 
 
Protocol deviations and adverse events will be documented, recorded, and promptly reported 
from the time of study enrollment through study discontinuation.  A Discontinuation CRF will be 
completed upon the subject’s 2-year study visit, or sooner if necessary. 
 

 
 
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2.5.4 Subject Surveys 
Miromatrix Medical Inc. has entered into an agreement with OptumInsight Life Sciences, Inc. to 
use the SF-36v2™ survey for this study.  SF-36v2™ is a 36-question quality-of-life survey that 
is commonly used in research, including hernia studies. It measures eight domains; four of these 
are related to physical heath, and four are related to mental health.  The physical health domains 
include physical functioning, physical role, bodily pain, and general health.  The mental health 
domains include vitality, social functioning, emotional role, and mental health.  Investigators 
may use and administer the Survey Materials only through investigational sites, only on behalf of 
Miromatrix Medical Inc., only during the Study Term (June 11, 2015 to March 31, 2018) and 
only for the Approved Purpose (MIROMESH PM-2).  Investigator sites may not use the Survey 
Materials for any other purpose.  Refer to Appendix C for additional details. 
 
The GERD Health Related Quality of Life (GERD-HRQL) survey will serve as a measurement 
tool for this study due to the close relationship between hiatal hernia and gastroesophageal reflux 
disease (GERD) symptoms.  The survey provides a quantitative method of measuring GERD 
symptom severity.  There are 51 possible scores, imparting the instrument with a high level of 
precision; and because of the response anchors, the instrument cannot have a floor effect.  A 
study by Velanovich also implies little ceiling effect.  The GERD-HRQL has been shown to be 
reliable, valid, and practical for the assessment of symptom severity in gastroesophageal reflux 
disease (7).   
 
In addition to the GERD-HRQL survey, subjects will be asked to complete symptom Visual 
Analog Scales (VAS) to assess the following hernia-related symptoms: regurgitation, chest pain, 
abdominal pain, nausea, vomiting, postprandial pain, cardiovascular, and pulmonary.  Subjects 
will be asked to indicate their symptoms over the previous 7 days by drawing a line on a 10-cm 
scale, with 0 representing ‘no effect on life’ and 10 representing ‘extreme effect on life’.   
 
2.5.5 Hernia recurrence 
Hernia recurrence is defined as a >2 cm protrusion of an organ through the esophageal opening 
in the diaphragm as identified on UGI (x-ray with barium contrast).  This definition is consistent 
with the definition of hernia recurrence for a previous study (8).  Recurrent hernias will be 
measured according to the distance from the apex of the hiatus to the posterior decussation of the 
left and right crus.  Classification categories for reporting purposes will be as follows: 
1) No evidence of recurrence 
2) ≤2 cm organ protrusion above diaphragm 
3) Between 2 and 4 cm organ protrusion above diaphragm 
4) >4 cm organ protrusion above diaphragm 
 
Asymptomatic recurrent hernias may not require reoperation but will still be reported on an 
Adverse Event CRF.  In the event of study site hernia recurrence requiring surgical treatment, a 
Re-intervention CRF will be completed and the subject will be discontinued from the study.   
2.5.5 Withdrawal of subjects due to non-compliance 
A minimum of three contact attempts will be made to schedule subjects for follow-up visits, 
including at least one written attempt.  After all attempts have been exhausted, a subject will be 
discontinued from the study.   

 
 
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2.5.6 Procedures to assess efficacy 
As an FDA cleared Class II medical device, the study device is generally regarded as efficacious.  
The procedures conducted in this study may provide insight on the extent and/or rate of vascular 
in-growth of the biological mesh and clinical acceptance of the study device.   
2.5.7 Procedures to assess safety 
As an FDA cleared Class II medical device, the study device is generally regarded as safe.  
Device-related and procedure-related adverse events will be collected throughout the study and 
will be reported according to applicable regulations as outlined in section 3.2. 
2.6 
Study outcome evaluations 
2.6.1 Study endpoints 
The primary endpoint is an assessment of hernia recurrence requiring surgical operation at two 
years post procedure for subjects that received implant of the mesh.  This assessment will be 
made at the 2-year follow-up visit.  Additionally, any subjects that had surgical hernia re-
intervention or the need for hernia re-intervention due to a recurrence according to the Adverse 
Event or Follow-Up CRF at any point in the previous two years post-procedure will be 
considered a failure. 
 
Secondary endpoints: 
• 
Assessment of hernia recurrence requiring surgical reoperation at one year post procedure 
for subjects that received implant of the mesh 
• Assessment of quality of life and symptomatic hernia recurrence using the SF-36, GERD-
HRQL, and symptom questionnaires at 2 weeks, 2 months, 6 months, 1 year, 18 months, 
and 2 years 
• Assessment of hernia recurrence >2 cm as seen on radiographic imaging at one year and 
two years post procedure in comparison to discharge imaging.   
• Assessment of device-related and procedure-related adverse events over time 
• 
Procedure characteristics for the hiatal hernia repair surgery will include at a minimum: 
− Length of hospital stay 
− Procedure time 
− Implant success 
2.6.2 Sample size determination 
This trial is an observational trial designed to gather long-term data for assessing performance of 
the Miromatrix Biological Mesh (MIROMESH®). Up to 50 subjects will be enrolled to provide 
data of hernia recurrence at two years post procedure in additional to long-term assessments of 
subject symptoms and quality of life.  There is no sample size calculation, but a sample size of 
30 is “rule of thumb” generally accepted as an adequate sample size for preliminary summaries.  
While the exact rate of success (no recurrence of hernia requiring success) is unknown to this 
study population, Table 3 below provides expected 95% confidence interval widths for various 
sample sizes and success using the binomial approach.  Using worst case scenario in the 
binomial distribution of 50%, the worst expected CI width will be in the 29-37% range with 
sample size of 30 to 50 subjects. 
 

 
 
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Table 3. Expected CI widths for the sample size and proportion of subjects free from hernia recurrence (binomial distribution, 2-
sided alpha of 0.05). 
Prop. 
Success 
Sample Size 
30 
35 
40 
45 
50 
50% (WCS) 
37.4% 
34.6% 
32.4% 
30.5% 
28.9% 
85% 
28.1% 
25.9% 
24.1% 
22.7% 
21.4% 
86% 
27.4% 
25.3% 
23.5% 
22.1% 
20.9% 
87% 
26.7% 
24.6% 
22.9% 
21.5% 
20.4% 
88% 
26.0% 
23.9% 
22.3% 
20.9% 
19.8% 
89% 
25.2% 
23.2% 
21.6% 
20.3% 
19.2% 
90% 
24.4% 
22.4% 
20.9% 
19.6% 
18.5% 
91% 
23.5% 
21.6% 
20.1% 
18.8% 
17.8% 
92% 
22.6% 
20.7% 
19.3% 
18.0% 
17.0% 
93% 
21.6% 
19.8% 
18.4% 
17.2% 
16.2% 
94% 
20.5% 
18.8% 
17.4% 
16.2% 
15.3% 
95% 
19.3% 
17.6% 
16.3% 
15.2% 
14.3% 
96% 
18.1% 
16.4% 
15.1% 
14.1% 
13.2% 
97% 
16.6% 
15.1% 
13.8% 
12.8% 
12.0% 
98% 
15.1% 
13.5% 
12.3% 
11.4% 
10.6% 
99% 
13.4% 
11.8% 
10.7% 
9.7% 
9.0% 
 
2.6.3 Outcome data and data analysis 
This trial is descriptive in nature with no pre-specified hypothesis.  Continuous data will be 
summarized using means, standard deviations, medians, ranges and possibly 95% confidence 
intervals. In addition, where assessments are made over time, the differences from baseline may 
be statistically tested to see if different from zero using paired Student’s t-test for parametric data 
or Wilcoxon Signed Rank test if non-parametric data.  An alpha of 0.05 will be considered 
statistically significant and no adjustments for multiple testing will be made. Categorical data 
will be presented as counts and percentages. 
 
Additionally, a Kaplan Meier survival analysis may be performed on the primary objective in 
case there are early withdrawals from the trial prior to the one year visit.  Otherwise, a sensitivity 
analysis may be performed plugging in best and worst case scenario results using binomial 
techniques. 
 
Summaries of the objectives will include all subjects with available data that received a 
MIROMESH implant and will include all assessments over time.  Procedure characteristics may 
include all subjects that had a MIROMESH implant attempt. 
 
Counts and incidences of adverse events will be summarized for all subjects with an implant 
attempted.  Summaries may be presented by seriousness and/or relatedness to procedure/device. 

 
 
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2.6.4 Data and Safety Monitoring Committee 
A Data and Safety Monitoring Committee will be not used due to the post-market nature of the 
clinical study with a cleared device to be used in accordance with current labeling.  Adverse 
events will be classified by investigators and will be reviewed by the study sponsor. 
3.0 
RISK ANALYSIS 
3.1 
Anticipated risks 
The study involves an FDA cleared, class II device with greater than minimal risk to the subject.  
The greater than minimal risk designation (as defined in 45 CFR Part 46) is solely due to the x-
ray imaging required at the discharge, 1-year, and 2-year visits.  Some of this imaging 
(specifically the discharge x-ray) may be considered standard of care at certain facilities.  
An x-ray of the upper GI tract provides an average radiation dose of 6 mSv.  This amount of 
radiation is comparable to the natural background radiation for 2 years, with an additional 
lifetime risk of fatal cancer from the examination estimated at 1 in 10,000 to 1 in 1,0001.  
Subjects in this study will be exposed to three such doses, all approximately one year apart. 
Anticipated risks of receiving the study device are the same regardless of whether a patient 
decides to participate in the study.  Known risks related to surgical mesh for hiatal hernia repair 
include, but are not limited to (9): 
 
• Infection 
• Pain 
• Adhesions 
• Erosion/migration 
• Compromised sterility 
• Bleeding 
• Mechanical failure 
• Foreign body reaction 
• Seroma 
• No in-growth 
• Mesh shrinkage 
• Hematoma 
There is a small risk of loss of confidentiality due to study participation.  
3.2 
Adverse event reporting  
For the purposes of this study, reportable adverse events will be limited to all events related to, 
or possibly related to, the study device and/or procedure.  There may be adverse events which 
meet the SAE definition but are not related to the device or procedure; such events will not be 
collected in this study.  The sponsor will determine if an event meets Medical Device Reporting 
(MDR) requirements.  All MDR reportable events will be reported to FDA as detailed in section 
3.2.5. 
3.2.1 Adverse event definitions 
Adverse Event: Any untoward medical occurrence associated with the use of a device in 
humans, whether or not considered device related. 
                                                          
1 http://www.radiologyinfo.org/en/safety/index.cfm?pg=sfty_xray  

 
 
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Adverse Device Effect: An adverse event caused by or related to the device.   
Serious adverse effect: An adverse effect is considered “serious” if, in the view of either the 
investigator or the sponsor, it results in any of the following outcomes:  
• death  
• a life-threatening AE 
• inpatient hospitalization or prolongation of existing hospitalization 
• a persistent or significant disability or permanent damage 
• a congenital anomaly/birth defect 
• intervention to prevent permanent impairment or damage. 
 
Life-threatening adverse effect: Any adverse effect that places the subject, in the view of either 
the investigator or the sponsor, at immediate risk of death from the effect as it occurred.  It does 
not include a reaction that, had it occurred in a more severe form, might have caused death. 
 
MDR-reportable event: events that manufacturers become aware of that reasonably suggest 
that one of their marketed devices may have caused or contributed to a death or serious injury, or 
has malfunctioned and the malfunction of the device or a similar device that they market would 
be likely to cause or contribute to a death or serious injury if the malfunction were to recur. 
3.2.2  Eliciting adverse effect information 
Clinical study subjects will be routinely questioned about adverse events at study visits. 
3.2.3  Recording and assessing of adverse effects 
All observed or volunteered reportable adverse effects (serious or non-serious) will be recorded 
in the subjects’ case histories.  Sufficient information will be pursued and/or obtained so as to 
permit 1) an adequate determination of the outcome of the effect (i.e., whether the effect should 
be classified as a serious adverse effect) and; 2) an assessment of the casual relationship between 
the adverse effect and the study device.    
Adverse effects believed to be associated with the study device will be followed until the effect 
(or its sequelae) resolves or stabilizes at a level acceptable to the investigator or until study 
completion, whichever is sooner. 
 
3.2.4 Causality and severity assessment 
The investigator will promptly review reportable adverse effects to determine 1) if there is a 
reasonable possibility that the adverse effect was caused by the study device or the study 
procedure; and 2) if the adverse effect meets the criteria for a serious adverse effect. 
3.2.5 Reporting MDR reportable events to the FDA 
The sponsor will electronically report MDR-reportable events to the FDA’s Center for Devices 
and Radiological Health according to the table below.   
 
Table 4. MDR Reporting Requirements 
What to report 
Reporting Timeframe 
30 day reports of deaths, serious injuries and 
malfunctions 
Within 30 calendar days of becoming aware of an 
event 

 
 
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What to report 
Reporting Timeframe 
5-day reports for an event designated by FDA or 
an event that requires remedial action to prevent 
an unreasonable risk of substantial harm to the 
public health 
Within 5 work days of becoming aware of an 
event 
 
Reports will consist of: 
• a completed Form FDA 3500A  
• a cover letter analyzing the significance of the event   
A copy of the report will be provided to all participating study investigators.   
Subsequent to the initial submission of a completed FDA Form 3500A, the sponsor will submit 
additional information concerning the reported adverse effect as requested by the FDA. 
3.2.6 Reporting adverse effects to the responsible IRB 
Reportable adverse events and follow-up information will be reported to the IRB according to 
the individual IRB’s policies.   
3.3 
Withdrawal of subjects due to adverse effects 
It is not expected that subjects will be withdrawn from the study due to adverse effects.  In the 
event that a subject experiences an adverse effect which results in removal of the study device, 
the subject should continue study participation until resolution of the event.  Upon resolution, the 
subject should be withdrawn from the study.    
4.0 
MONITORING PROCEDURES 
Monitoring of the study for compliance with the clinical protocol and with applicable regulations 
will be conducted periodically by the sponsor and/or a designated CRO or equivalent.   
 
The investigator and the institution will permit direct access of the study monitors and 
appropriate regulatory authorities to the study data and to the corresponding source data and 
documents to verify accuracy.  In cases of institution policy which limit sponsor access to 
medical records, the institution will be required to provide adequate resources and procedures to 
ensure data quality and accuracy. 
 
The study Monitoring Plan will be located in the sponsor’s electronic study master file. 
5.0 
LABELING 
The Instructions for Use document is located in Appendix A. 
6.0 
INFORMED CONSENT 
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. 

 
 
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The sponsor will work with study site personnel to provide an informed consent form and 
HIPAA authorization to the IRB for approval.  The written consent document will embody the 
elements of informed consent as described in CFR 21 CFR 50.25 and will also comply with local 
regulations. The Investigator will retain an IRB-approved copy of the Informed Consent Form in 
the study master file. 
A properly executed, written, informed consent will be obtained from each subject prior to 
conducting any study-related procedures.  Information should be given in both oral and written 
form and subjects (or their legal representatives) must be given ample opportunity to inquire 
about details of the study.  If a subject is unable to sign the informed consent form (ICF) and the 
HIPAA authorization, a legal representative may sign for the subject.   A copy of the signed 
consent form will be given to the subject or legal representative of the subject and the original 
will be maintained with the subject’s study records at the site. 
7.0 
IRB INFORMATION 
The protocol and consent form will be reviewed and approved by the IRB of each participating 
center prior to study initiation.  Adverse events 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.  
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 and the Sponsor before the study is initiated.  This 
approval must refer to the study by exact protocol title 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 approved should be obtained.   
The IRB must be informed of revisions to other documents originally submitted for review; 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. 
8.0 
ADDITIONAL RECORDS AND REPORTS   
8.1 
Data handling and record-keeping 
Sample Case Report Forms (CRFs) are located in Appendix B.  Paper CRFs will be used for this 
study and will be entered into a validated MS Excel spreadsheet using a 2-step process to ensure 
accuracy.  At a minimum, an Enrollment CRF and a Discontinuation CRF will be completed for 
each subject enrolled into the clinical study.  The investigator will review and sign each 
completed CRF; the investigator’s signature serving as attestation of the investigator’s 
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Source Data are the clinical findings and observations, laboratory and test data, and other 
information contained in Source Documents.  Source Documents are the original records (and 
certified copies of original records); including, but not limited to, hospital medical records, 
physician or office charts, physician or nursing notes, evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, x-rays, etc.  When applicable, information 
recorded on the CRF shall match the Source Data recorded on the Source Documents.   
Patient survey CRFs will be considered Source Documents when used as the original source (i.e. 
they are completed directly by the subject, or the subject’s responses are recorded directly onto 
the CRF by site personnel).   
8.2 
Record maintenance and retention  
 
The investigator will maintain the following study records: 
• 
IRB correspondence (including approval notifications) related to the clinical protocol, 
including copies of adverse event reports and annual or interim reports 
• 
All versions of the IRB-approved clinical protocol and corresponding IRB-approved 
consent form(s) 
• 
Signed Clinical Trial Agreement, Investigator’s Agreements and Financial Disclosures 
• 
Curriculum vitae for Investigators 
• 
Training documentation for all study site personnel 
• 
Signed informed consent forms 
• 
Completed study worksheets (if used), signed and dated by investigator or delegated site 
personnel 
• 
Source Documents or certified copies of Source Documents 
• 
Monitoring visit communications 
• 
Copies of sponsor notifications of adverse effect information 
 
The sponsor will maintain the following study records: 
• 
Copies of submitted Form FDA 3500A, notice of device recalls 
• 
IRB correspondence (including approval notifications) related to the clinical protocol;  
• 
All versions of the IRB-approved clinical protocol and corresponding IRB-approved 
consent form(s) 
• 
Signed Clinical Trial Agreement, Investigator’s Agreements and Financial Disclosures 
• 
Curriculum vitae for Investigators 
• 
Training documentation for all study site personnel 
• 
Monitoring visit reports and communications 
• 
Corrective and Preventative Action (CAPA) Plans, if applicable 
• 
Adverse effect communications to sites 
• 
Final clinical study report 
 

 
 
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Subject study binders which include identifying information will be stored in a locked cabinet or 
office (or similar locked location) at the study sites.  Subject confidentiality will be protected by 
the use of unique subject IDs in the electronic database (MS Excel spreadsheet).  Subject 
identifying information will not be collected in the database.  Additionally, subject names or 
other directly identifiable information will not appear on study reports, publications, or other 
disclosures of clinical study outcomes. 
Investigators will retain the specified records and reports for a minimum of two years after the 
investigation has been discontinued.  Investigators may seek sponsor approval to transfer custody 
of the records to any other person or entity who will accept responsibility for them. 
9.0 
PUBLICATIONS   
9.1 
Authorship 
The study sponsor will be responsible for determining publication procedures and resolving 
authorship issues.  Authorship may be determined by various means, including contribution to 
the study design and enrollment rate.   
9.2 
Trial Registration 
The International Committee of Medical Journal Editors (ICMJE) member journals have adopted 
a clinical trials registration policy as a condition for publication.  The ICMJE defines a clinical 
trial as any research project that prospectively assigns human subjects to intervention or 
concurrent comparison or control groups to study the cause-and-effect relationship between a 
medical intervention and a health outcome.  Medical interventions include drugs, surgical 
procedures, devices, behavioral treatments, process-of-care changes, and the like.  Health 
outcomes include any biomedical or health-related measures obtained in patients or participants, 
including pharmacokinetic measures and adverse events. The ICMJE policy requires that all 
clinical trials be registered in a public trials registry such as ClinicalTrials.gov, which is 
sponsored by the National Library of Medicine.  The sponsor will register this trial on 
ClinicalTrials.gov in order for the research results to be considered for publication in ICMJE 
member journals.   
 
 
 

 
 
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References 
1. Breaking Free of Sample Size Dogma to Perform Innovative Translational Research. Bacchetti, Peter, 
Deeks, Steven G and McCune, Joseph M. 2011, Science Translational Medicine, p. 87ps24. 
2. Guidelines for the management of hiatal hernia. Kohn, Geoffrey Paul, et al. 27, New York : Springer 
Science+Business Media, 2013, Surgical Endoscopy, pp. 4409-4428. 
3. Hiatal hernia repair with biologic mesh reinforcement reduces recurrence rate. Schmidt, E, et al. 27, 
Jan 2014, pp. 13-17. 
4. The safety of biologic mesh for laparoscopic repair of large, complicated hiatal hernia. Wassenaar, 
Eelco B., et al. 26, 2012, Surgical Endoscopy and Other Interventional Techniques, pp. 1390-1396. 
5. The surgical treatment of paraesophageal hernias. Feo, Carlo V., Zuolo, Michele and Patti, Marco G. 
84, Ferrara, Italy : s.n., 2013, Annali Italiani di Chirurgia, pp. 257-262. Published online 29 October 2012. 
6. Rapamycin, but not cyclosporine A, inhibits vascularization and incorporation of implanted surgical 
meshes. Laschke, Matthias W., et al. 6, 2009, Vol. 22, pp. 654-662. 
7. The development of the GERD-HRQL symptom severity instrument. Velanovich, V. 20(2), 2007, 
Diseases of the Esophagus, pp. 130-4. 
8. Biological Prosthesis Reduces Recurrence After Laparoscopic Paraesophageal Hernia Repair. 
Oelschlager MD, Brant K., et al. 4, s.l. : Annals of Surgery, October 2006, Vol. 244, pp. 481-490. 
9. Major mesh-related complications following hernia repair. Robinson, T.N., et al. 2005, Surgical 
Endoscopy And Other Interventional Techniques, pp. 1556-1560.