Minimally Invasive Fetoscopic Regenerative Repair of Spina Bifida - A Pilot Study
Phase: NA
Conditions: Spina Bifida, Myelomeningocele, Neural Tube Defects
Sponsor: Rodrigo Ruano

Fetoscopic Repair of Spina Bifida 
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Rodrigo Ruano, MD 
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MINIMALLY INVASIVE FETOSCOPIC REGENERATIVE 
REPAIR OF SPINA BIFIDA - A PILOT STUDY
Initial version: [10/4/2018] Version (1.0) 
Revised: 
[11/7/2018] Version [1.1] (Tracked Changes) 
Revised: 
[11/7/2018] Version [2.0] (Clean)  
Revised: 
[11/20/2018] Version [2.1] (Tracked Changes) 
Revised: 
[11/20/2018] Version [3.0] (Clean)  
Revised: 
[12/11/2018] Version [3.1] (Tracked Changes) 
Revised: 
[12/11/2018] Version [4.0] (Clean)  
Revised: 
[04/08/2019] Version [4.1] (Tracked Changes) 
Revised: 
Revised: 
Revised:           
Revised: 
Revised:  
Revised:  
Revised:  
Revised:  
Revised:   
Revised:            
[04/08/2019] Version [5.0] (Clean)  
[06/04/2019] Version [5.1] (Tracked Changes) 
[06/04/2019] Version [6.0] (Clean) 
[07/22/2019] Version [6.1] (Track Changes) 
[07/22/2019] [Version 7.0] (Clean) 
[02/04/2020] [Version 7.1] (Track Changes) 
[03/02/2020] [Version 7.2] (Track Changes) 
[03/02/2020] [Version 8.0] (Clean) 
[01/28/2021] [Version 8.1] (Track Changes) 
[01/28/2021] [Version 9.0] (Clean) 
Principal Investigator 
Dr. Edward S. Ahn, MD  
Mayo Clinic  
200 First Street SW  
Rochester, MN 55905  
Telephone Number: 507-284-2376 
Fax Number: 507-266-7953  
E-mail Address: Ahn.Edward@mayo.edu
Regulatory Sponsor:  
Dr. Rodrigo Ruano 
Telephone Number:  832-418-3310 
Protocol Number: (IRBe) 
18-008622
IDE Number:  
G180245
NCT03936322

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Table of Contents  
STUDY SUMMARY .................................................................................................................... 4 
1  INTRODUCTION ..................................................................................................................... 5 
1.1  BACKGROUND ........................................................................................................................ 5 
1.2  INVESTIGATIONAL DEVICE ...................................................................................................... 6 
1.3  PRECLINICAL DATA ................................................................................................................ 6 
1.4  CLINICAL DATA TO DATE ........................................................................................................ 7 
1.4.1  Unpublished data: ......................................................................................................... 7 
1.4.2  Published Clinical Investigations ................................................................................. 8 
1.5  STUDY RATIONALE AND RISK ANALYSIS (RISKS TO BENEFITS RATIO) ...................................... 11 
1.5.1 Study Rationale ............................................................................................................ 11 
1.5.2 Anticipated Risks .......................................................................................................... 11 
1.5.3  Risk Minimizing Procedures and Activities ................................................................ 15 
1.5.4  Risk/Benefit Analysis ................................................................................................... 15 
1.6 ANTICIPATED DURATION OF THE CLINICAL INVESTIGATION .................................................... 16 
2 STUDY OBJECTIVES............................................................................................................ 16 
3  STUDY DESIGN ..................................................................................................................... 17 
3.1  GENERAL DESIGN ................................................................................................................ 17 
3.2  PRIMARY STUDY ENDPOINTS ................................................................................................. 17 
3.3  SECONDARY STUDY ENDPOINTS ............................................................................................ 18 
4  SUBJECT SELECTION, ENROLLMENT AND WITHDRAWAL ................................. 18 
4.1  INCLUSION CRITERIA ............................................................................................................ 19 
4.2  EXCLUSION CRITERIA ........................................................................................................... 19 
4.3  SUBJECT RECRUITMENT, SCREENING AND ENROLLMENT ....................................................... 20 
4.4  EARLY WITHDRAWAL OF SUBJECTS ....................................................................................... 21 
4.4.1  When and How to Withdraw Subjects ......................................................................... 21 
4.4.2  Data Collection and Follow-up for Withdrawn Subjects............................................ 21 
5  STUDY DEVICES .................................................................................................................. 22 
5.1  PREPARATION OF INVESTIGATIONAL DEVICES ....................................................................... 22 
5.2  PACKAGING AND LABELING .................................................................................................. 23 
5.3  RECEIVING, STORAGE, DISTRIBUTION AND RETURN ............................................................... 23 
5.3.1  Receipt of Investigational Devices .............................................................................. 23 
5.3.2  Storage ........................................................................................................................ 23 

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5.3.3  Device Accountability ................................................................................................. 23 
6  STUDY PROCEDURES......................................................................................................... 23 
6.1  VISIT 1 – SCREENING VISIT ................................................................................................... 23 
6.2  VISIT 2 – FETOSCOPIC PROCEDURE TO REPAIR MMC ........................................................... 24 
6.3  WEEKLY POSTSURGICAL VISITS – POSTSURGICAL MANAGEMENT BEFORE DELIVERY (V3 
FOLLOW-UPS) ............................................................................................................................. 26 
6.4  DELIVERY (V4)..................................................................................................................... 26 
6.5  POSTNATAL FOLLOW-UP VISIT (V5) ...................................................................................... 27 
6.6 LONG-TERM FOLLOW-UP, 12 MONTHS OF AGE (V6) ............................................................. 27 
6.7 LONG-TERM FOLLOW-UP, 60 MONTHS OF AGE END OF STUDY (V7-V10) .............................. 27 
6.8  UNSCHEDULED VISITS .......................................................................................................... 28 
6.9  SCHEDULE OF EVENTS TABLE ............................................................................................... 28 
7  STATISTICAL PLAN ............................................................................................................ 29 
7.1  SAMPLE SIZE DETERMINATION .............................................................................................. 29 
7.2  STATISTICAL METHODS ......................................................................................................... 29 
7.3  SUBJECT POPULATION(S) FOR ANALYSIS ............................................................................... 30 
8  SAFETY MANAGEMENT AND ADVERSE EVENTS ..................................................... 30 
8.1  STOPPING RULES ................................................................................................................. 31 
8.2  CLINICAL ADVERSE EVENTS .................................................................................................. 31 
8.3 DEFINITION OF AN ADVERSE EVENT ....................................................................................... 31 
8.4 DEFINITION OF UNANTICIPATED ADVERSE DEVICE EFFECT (UADE) ..................................... 32 
8.5  DEFINITION OF A SERIOUS ADVERSE EVENT (SAE) ................................................................ 32 
8.5.1  Relationship of SAE to study device or other intervention ......................................... 33 
8.5.2 Severity of Adverse Events ........................................................................................... 33 
8.5.3 Eliciting Adverse Event Information ............................................................................ 34 
8.5.4  Recording Adverse Events .......................................................................................... 34 
8.6  ADVERSE EVENT REPORTING ................................................................................................ 35 
8.6.1  Adverse Event Reporting Period ................................................................................. 35 
8.6.2  IRB Notification of SAEs and Other Unanticipated Problems ................................... 36 
8.6.3  Sponsor-Investigator Reporting: Notifying the FDA .................................................. 36 
8.6.4  Deviations from the investigational plan .................................................................... 37 
8.6.5  Follow-up Reports....................................................................................................... 37 
8.6.6  General Physical Examination Findings .................................................................... 38 
8.7  MEDICAL MONITORING ........................................................................................................ 38 
8.7.1  Independent Data and Safety Monitoring Board ........................................................ 38 
9  DATA HANDLING AND RECORD KEEPING ................................................................. 42 
9.1  CONFIDENTIALITY ................................................................................................................ 42 
9.2  SOURCE DOCUMENTS ........................................................................................................... 42 
9.3  CASE REPORT FORMS ........................................................................................................... 42 
9.4  RECORDS RETENTION ........................................................................................................... 43 
10  STUDY MONITORING, AUDITING, AND INSPECTING............................................ 43 
10.1  STUDY MONITORING PLAN ................................................................................................. 43 

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10.2 AUDITING AND INSPECTING ................................................................................................. 44 
11 ETHICAL CONSIDERATIONS .......................................................................................... 44 
12  STUDY FINANCES .............................................................................................................. 44 
12.1  FUNDING SOURCE .............................................................................................................. 44 
12.2 CONFLICT OF INTEREST ....................................................................................................... 45 
13 PUBLICATION PLAN ......................................................................................................... 45 
14  REFERENCES ...................................................................................................................... 45 
 
  
  
 
LIST OF ABBREVIATIONS  
AE  
Adverse Event/Adverse Experience  
CFR  
Code of Federal Regulations  
CO2  
Carbon Dioxide  
CRF  
Case Report Form  
CSF  
Cerebral Spinal Fluid  
DSMB  
Data and Safety Monitoring Board  
FDA  
Food and Drug Administration  
fSBA  
Fetal Spina Bifida Apperta  
GCP  
Good Clinical Practice  
HIPAA  
Health Insurance Portability and Accountability Act 
IDE  
Investigational Device Exemption  
IRB  
Institutional Review Board  
MMC  
Myelomeningocele (Spina Bifida)  
PHI  
Protected Health Information  
PI  
Principal Investigator  
PPROM  
Premature Rupture of the Membranes  
SAE  
Serious Adverse Event/Serious Adverse Experience  
SOP  
Standard Operating Procedure  
UADE  
 
 
 
Unanticipated Adverse Device Effect  
 
 
Study Summary  
Title  
Minimally Invasive Fetoscopic Regenerative Repair of Spina Bifida – 
A Pilot Study  
Running Title  
Fetoscopic Repair of Spina Bifida  

Fetoscopic Repair of Spina Bifida  
  
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IRB Protocol 
Number  
18-008622  
Phase  
Pilot  
Methodology  
Un-blinded, non-randomized, single arm   
Overall Study 
Duration  
The investigation is anticipated to take 5-10 years.  
Subject Participation 
Duration  
Each subject will be in the study for 60 months.  
Objectives  
The primary objective is to investigate the feasibility of performing 
this minimally invasive fetal surgical repair of myelomeningocele 
(MMC).  
Number of Subjects  
15  
Diagnosis and Main 
Inclusion Criteria  
Pregnant women - maternal age 18 years or older with a singleton 
pregnancy diagnosed with MMC and evidence of hindbrain 
herniation.  
Statistical  
Methodology  
Descriptive Statistical Analysis  
  
  
  
  
  
1 Introduction  
This document is a protocol for a human research study. This study will be carried out in 
accordance with the procedures described in this protocol, applicable United States 
government regulations and Mayo Clinic policies and procedures.   
1.1  Background  
Fetal spina bifida is a devastating neurological congenital anomaly characterized by a closure 
defect of the spinal column. It results from incomplete closure of the neural tube between 22 
and 28 embryological days. Its incidence is approximately 1-2 per 1,000 births. It is 
considered the most common congenital anomaly of the central nervous system that is 
compatible with life. (1)  
  
1. 
The most frequent form is myelomeningocele (MMC), characterized by 
the extrusion of the spinal cord into a sac filled with cerebrospinal fluid 
(CSF), and is associated with lower limb paralysis and bowel and bladder 
dysfunction.  
  

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2. 
The majority of MMC can be diagnosed with ultrasound during the first 
and second trimesters, with diagnosis often occurring between 14 and 20 
weeks of gestation following maternal serum screening and detailed fetal 
ultrasound.(2-5)   
  
3. 
Fetal MMC is usually associated with an Arnold-Chiari II malformation, 
which includes a constellation of anomalies such as hindbrain herniation, 
brainstem abnormalities, low-lying venous sinuses and a small posterior 
fossa. (6-7) This malformation is associated with different degrees of 
hydrocephalus. The Arnold-Chiari II malformation has well-known 
deleterious effects on motor, cranial nerve and cognitive functions. (6-7) 
Postnatally some form of CSF-peritoneal shunt is frequently required, 
often resulting in a lifelong requirement for monitoring due to the 
frequent complications such as shunt failure, migration and infection. (6, 8- 
10 
  
  
1.2  Investigational Device  
  
This study will use multiple devices for the surgical procedures as part of this investigation. 
They were introduced into commercial distribution on or after May 28, 1976 and have been 
determined substantially equivalent to a device in commercial distribution or are otherwise 
approved for clinical use. These devices may be used off label without trying to support a 
change in labeling. By nature, this study will be testing the safety and effectiveness of the 
devices.  Additional detailed information about the devices is available in Section 5 of this 
protocol.  
  
1.3  Preclinical Data  
  
Experimental studies using animal models have shown that prenatal coverage of a spina 
bifida-like lesion can preserve neurological function and reduce or reverse hindbrain 
herniation.(9, 11-14)   These studies suggest a “two-hit” hypothesis in which the ultimate 
neurologic deficit results from a combination of the failure of normal neural-tube closure 
(first hit) with secondary spinal cord injury resulting from prolonged exposure of sensitive 
neural elements to the amniotic fluid (second hit mechanism).(15-16)  
  
Our group developed a technique to treat fetoscopically the spina bifida in a sheep model 
using intrauterine carbon dioxide as a distension medium in a sheep model. We demonstrated 
safety and efficacy of this technique in repairing fetal spina bifida. (17)  

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1.4  Clinical Data to Date  
1.4.1 Unpublished data:   
Using the knowledge and expertise gained with more than 3 years of experience in fetoscopic 
sheep surgery, our group leading by Dr Michael Belfort (where Dr. Rodrigo Ruano was part 
of the group before joining Mayo Clinic), in collaboration with a group in Barcelona (Peiro et 
al (17)), has developed a novel approach for the minimally invasive repair of fetal neural tube 
defects. This technique has now been employed in 7 human cases in Barcelona, Spain, 1 in 
Mexico City, Mexico and 1 in Shiraz, Iran showing its feasibility and applicability to the 
human uterus and fetus, and demonstrating an improved degree of flexibility in terms of 
access to the fetus regardless of placental location. The technique is designed to decrease the 
maternal risks of open fetal surgery while maintaining a similar level of fetal benefit as seen 
in the randomized controlled trial that compared fetal intervention versus postnatal therapy 
for spina bifida, which was called the MOMS trial. (18)  
  
Our technique employs an open abdomen/closed uterus methodology that allows significantly 
more flexibility in the minimally invasive portion of the fetal neural tube repair while at the 
same time allowing a closed skin repair in a similar manner to that employed at Mayo Clinic 
using an open uterus approach. In the 9 human cases performed in Barcelona, Mexico City 
and Shiraz there has not been any incidence of maternal premature rupture of the membranes 
(PPROM) except for 1 case at 35+ weeks. One pregnancy was delivered at 28 weeks 
(Mexico). The 9 patients have all been delivered by cesarean section and 7 were by elective 
late term CS (37+ weeks), one was at 35+ weeks because of PPROM, and 1 (in Mexico) was 
at 28 weeks from preterm labor. All babies have done well except for 1 in Mexico who died 
from prematurity.  
  
We have shown in 8 human cases that the placode can be satisfactorily dissected free of the 
skin using micro-scissors and that the skin edges can be successfully undermined 
fetoscopically. We have shown in 7 of these cases that a patch of bovine pericardium can be 
placed over the placode and that the patch can be covered with sealant. In the last 2 cases, the 
skin edges were sutured with a V-loc suture showing that this technique is also feasible.  
  
The technique employs a novel approach to low pressure uterine distention using the same 
carbon dioxide gas (14, 19-22) that others attempting fetoscopic repair have used, but employing 
a much lower gas flow rate and pressure. In addition, our technique allows a significantly 
quicker neural tube repair because of improved access to the fetus, ability to manipulate the 
fetus into the required position, and superior port placement resulting from the exteriorized 
maternal uterus. In addition, because of the exteriorized uterus and the superior placement 
this allows, we require only two access ports and these can be sutured into the uterus 
allowing a closed seal and minimizing gas leakage. Finally, recent advances in miniature 
surgical instruments (Storz 1.5 - 3mm surgical sets) allow unprecedented flexibility which 
enables a full surgical repair to be performed via a fetoscopic approach.  
  

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Before considering clinical implementation of fetal endoscopic myelomeningocele closure as 
standard care, the frequency of complications should be appropriately reduced and results 
assessed in larger groups over a longer period of time.  
1.4.2 Published Clinical Investigations  
  
The recent publication of the NICHD sponsored randomized controlled trial (MOMs Trial  
(18) 
) demonstrated clear neonatal benefit of open in-utero fetal surgical repair of MMC. The 
study showed a reduction in neurological morbidity, especially in terms of decreased severity 
of hydrocephalus and in degree of hindbrain herniation (relative risk: 0.67; 95% confidence 
interval: 0.56-0.81, and need for postnatal ventricular-peritoneal shunting (risk relative: 0.48, 
95% confidence interval: 0.36–0.64).  
  
Open in-utero fetal surgery is not without risk and the MOMS Trial showed an elevation in 
maternal-fetal morbidity/risk when compared to the postnatally treated group, including 
higher risk for chorioamniotic separation (26% vs. 0%, respectively), maternal pulmonary 
edema (6% vs. 0%), oligohydramnios (21% vs. 0%), placental abruption (6% vs. 0%), 
spontaneous membrane rupture (46%; RR: 6.15; 95% CI: 2.75-13.78), spontaneous labor 
(38%; RR: 2.80, 95% CI: 1.51-5.18), maternal blood transfusion (9%; RR: 7.18; 95% CI:  
0.90-57.01), and preterm delivery before 34 weeks (46%; RR: 9.2; 95% CI: 3.81 2.19).(18)  
The reason for the increased incidence of these complications was related to the nature of the 
open fetal procedure, which involves a multi-faceted invasive approach including maternal 
laparotomy, large hysterotomy with uterine edge stapling, and open fetal repair of the spina 
bifida defect that may involve manipulation and exposure of the fetus for a significant 
amount of time.  
  
Fetal endoscopic surgery has progressed rapidly over the past decades and we are now able to 
perform a number of intricate procedures inside the uterus with specially designed 
instruments. These procedures include laser therapy for Twin-twin-transfusion syndrome, 
fetal cystoscopy and fulguration of posterior urethral valves, release of amniotic bands, and 
placement of various shunts and balloons inside fetal structures and cavities (peritoneal, 
pleural, cardiac, and trachea).  
  
  
  
  
Fetoscopy offers a less invasive therapeutic option that could reduce a number of the 
morbidities (both maternal and fetal) related to open fetal procedures. (21-25)  A few animal 
studies and some clinical human experience with fetoscopic repair of MMC have been 
reported showing the feasibility of covering the defect with a patch and sealant, or even in 
performing a full repair. These repairs have been accomplished using at least two (and 
sometimes more) entry ports through the uterine wall.(20, 25  Kohl et al., in Germany, have 
demonstrated the feasibility of performing a complete percutaneous fetoscopic repair of 
MMC using carbon dioxide to distend the uterus and provide a dry working area for the 
surgeon to perform the repair.(24, 26)  These investigators described a two-layer covering 

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technique using an absorbable patch (Durasis, Cook, Germany) and sutures. However, while 
they showed that the procedure is feasible; their percutaneous technique with complete two 
layer surgical closure of the defect using sutures was associated with prolonged operative 
time and significant maternal and obstetrical morbidities.  
  
The Kohl group used 3 uterine trocar insertions through an intact maternal abdominal wall, 
each external trocar having a diameter of 5 mm. Their technique also involved multiple CO2 
gas infusion ports in order to maintain adequate distension of the uterine cavity for the 
surgery to be carried out. The frequency of preterm birth and rupture of the membranes using 
their technique is higher than that observed in those cases that have had open fetal surgery. 
As a result, the fetoscopic approach as described by Kohl et al, has not been popularized nor 
accepted internationally.  
  
Their reports however, have stimulated most fetal surgery groups worldwide to explore the 
potential of a less invasive methodology for fetal neural tube repair and active programs in 
this regard are ongoing at different fetal centers in the world. There is no question that the 
field is ready for a less invasive methodology than what is currently available with open fetal 
repair.  
  
The value of the Kohl experience has been in proving that CO2 insufflation in the uterus is 
not toxic to either mother or fetus and is well tolerated by both without evidence of fetal or 
maternal academia. (27)   In their 37 procedures, 36 were successful without maternal or fetal 
complication intra-operatively. In one case acute membrane rupture occurred during the 
surgery - a not uncommon complication during any fetoscopic procedure regardless of the 
use of CO2. In a second case, maternal bleeding occurred when one of the trocars was 
removed after the surgery.  
  
A recent publication by Verbeek et al (28) showed that in fetal endoscopic repair of spina bifida 
aperta (fSBA), on average, the fSBA group were born at a lower gestational age than the 
neonatally repaired spina bifida aperta (nSBA) group (median 32 wks [range 25-34 wks] vs 39 
wks [34-41 wks]; p=0.001). The fSBA were all operated on by Tomas Kohl’s group in Bonn, 
Germany, while the neonatal repair group were operated on in Groeningen in Holland. The 
fSBA group experienced more complications (chorioamnionitis 3/13 (23%), premature rupture 
of the amniotic membranes 11/13 (85%), oligohydramnios 8/13(62%), and infant respiratory 
distress syndrome necessitating intermittent positive-pressure ventilation 10/13 (77%). (28)  
In their paper regarding fSBA patients Kohl et al. reported a maternal complication rate from 
hemorrhage of 19% (3/16). In two of these cases there was minor placental bleeding during 
the procedure from inadvertent trauma, while in one case one of the trocars was inadvertently 
placed through an anterior placenta and resulted in heavy placental bleeding. It should be 
remembered that Kohl et al have employed a technique that utilizes a minimum of 3 trocars 
and frequently more, and a procedure time of a median of 4 hours (range 5 minutes to 8 
hours). Compared to open spina bifida repair in the MOMS trial the complication numbers 
are high: chorioamnionitis – 23% vs. 3%, PPROM 85% vs. 46%, oligohydramnios – 62% vs. 
21%, In terms of neurological function however, Verbeek et al (28) noted better preservation 

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after fSBA than after nSBA (median motor and sensory gain of two segments; better 
preserved knee-jerk [p=0.006] and anal [p=0.032] reflexes). (28)  
  
The intra-individual difference in leg muscle ultrasound density was smaller in fSBA than in 
nSBA infants (mean difference 24, 95% confidence interval [CI] 15-33; p<0.05), which was 
associated with better preserved segmental muscle function. Verbeek et al (28) concluded that 
fetal endoscopic surgery is associated with spinal segmental neuroprotection, but that it 
results in more complications.  
  
To date, I was part of some surgeries performed at Texas Children’s Hospital/Baylor College 
of Medicine. We have performed one initial case that was published in the Obstetrics and 
Gynecology journal. (29)  This case was performed under a Baylor College of Medicine IRB 
approved protocol investigating the surgical approach prior to becoming aware that an IDE 
was required. AC is a 25 year old gravida 2 para 1 patient with one prior term vaginal 
delivery, presented with a fetus who had a known open neural tube defect. She fulfilled all of 
the requirements for open neural tube repair per the MOMS criteria. Patient AC was 
originally offered the standard open procedure and consented to the open procedure. She was 
then (per protocol) apprised of the fetoscopic procedure and she fully understood the 
procedure and the risks and benefits. She underwent the surgery on 7/30/2014 at 23 weeks 
gestation. The surgery was uneventful, performed per protocol, and the neural tube defect 
was closed as expected. There were no complications with the surgery or postoperative 
course and the patient was discharged to an outpatient facility (Ronald McDonald House) 
where she remained until 09/03/2014. On that date, at 28-2/7 weeks she presented with 
ruptured membranes and was hospitalized and managed as for routine preterm premature 
rupture of the membranes with latency antibiotics (ampicillin and azithromycin). She 
remained in hospital on bedrest until the baby was delivered by cesarean section (breech 
presentation) on 9/21/2014 at 30-6/7 weeks because of a fetal tachycardia and non-specific 
concern for fetal wellbeing. The baby (GC) did well and had Apgar scores of 8 and 9 at 1 and 
5 minutes respectively. He did not require any resuscitation and had excellent cord blood 
gases with a pH of 7.37 and BE of -0.4. . This baby was discharged home on room air and 
needed a ventriculo-peritoneal shunt.  
  
  
  
  
Most recently, Kohl et al have published his experience considering technique, maternal 
outcomes and postnatal outcomes. (30-32) The Germany group have demonstrated that 
fetoscopic repair of spina bifida was safer for the mothers (no cases of maternal demise, 
spontaneous labor, placental abruption or need for transfusion) with similar postnatal 
outcomes [Ventriculoperitoneal shunt placement within 1 year was required in 45% of the 
cases] when compared to the MOMs trial. However, the Germany group has described high 
rates of premature rupture of the membranes (PPROM) [84.3%, mean gestational age at 29.7 
(range, 22.6-37.3) weeks] and prematurity [Mean gestational age at delivery was 33 (range, 
24.6-38.1) as they perform the fetoscopic procedure using 5 ports and bigger instruments 
than our group.  

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Our group published our experience with 28 patients with 22 patients undergoing fetoscopic 
repair of spina bifida. (33)  We demonstrated that improvement of the surgical technique 
allowed for better outcomes, leakage of cerebrospinal fluid in 10%, postnatal hydrocephalus 
in 30%, vaginal delivery in 60% and premature rupture of the membranes in 10%. The 
outcomes related to the fetus were very similar to the open fetal repair, but with significant 
reduction of maternal morbidity.  
1.5  Study Rationale and Risk Analysis (Risks to Benefits Ratio)  
1.5.1 Study Rationale  
  
The novel portions of this surgery will be;  
1) the approach to the uterus and the use of a minimally invasive technique with 
CO2 gas within the uterus and 2) a two-three port approach.   
  
In this procedure, the maternal abdomen will be opened via a laparotomy incision and the 
uterus will be exteriorized with the fetus in-situ. Once the uterus is exteriorized the fetus can 
be manipulated through the wall of the uterus into an ideal position for the surgery, 
regardless of the placental location. A small volume of amniotic fluid (+/- 200cc) will be 
withdrawn through an 18G needle (placed under ultrasound guidance) prior to starting the 
fetoscopic portion of the surgery, and replaced with carbon dioxide gas at a pressure of less 
than 20 mmHg. This is sufficient to inflate the uterus to a degree that clearly exposes the fetal 
back and the spina bifida defect. The PI has participated in at least 10 procedures and the 
coinvestigator has performed more than 15 procedures now with duration of CO2 gas in the 
uterus from 1-4 hours without any maternal or fetal complication.  
  
The fetus remains partially submerged in the amniotic fluid and only the back is exposed to 
the gas. One 12F and one to two  6F-12F vascular access port will be placed in ideal 
positions for maximal visualization and access. Using standard FDA approved/cleared 
surgical equipment the neural tube defect will be endoscopically repaired using standard 
minimally invasive dissection and suturing techniques.  
  
  
  
  
1.5.2 Anticipated Risks  
  
There are a number of maternal and fetal risks associated with the neural tube defect repair 
procedure.  
  
1.5.2.1 Anticipated Maternal Risks  
  

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1. 
Amniotic fluid leakage into the maternal abdomen, leading to peritoneal irritation. 
This does not require any therapeutic intervention.  
  
2. 
Chorioamniotic separation  
  
3. 
Bleeding (in the absence of placental abruption) can occur from the uterine entry 
site leading to hemoperitoneum. This is usually self-limited but the patient needs 
to be monitored closely and if necessary treated with a blood transfusion. 
Prevention consists of ultrasound-guided insertion.  
  
4. 
Local wound infection at the trocar and/or laparotomy sites occurs in less than 5% 
of cases and is managed by the administration of antibiotics and/or local drainage.  
  
5. 
Regional analgesia can be complicated by postdural puncture headache, failed 
sensory blockage, infection, hematoma, neurologic injury, and drug side-effects 
(pruritus, nausea and vomiting, urinary retention, hypoventilation, seizure, 
hypotension). The incidence of these complications is very low and no different 
than for other conditions where loco-regional is offered.  
  
6. 
General anesthesia has known complications including death, brain injury, 
asphyxia, hypotension and damage to lungs, larynx, pharynx and teeth.  
  
7. 
Possible side-effects of the drugs commonly used after fetal surgery include: a. 
Magnesium sulfate - flushing, sweating, muscle weakness, nausea and vomiting, 
lethargy, blurred vision, excess fluid in the lungs necessitating supplemental 
oxygen; b. indomethacin - intestinal cramping, decreased amniotic fluid 
production, and constriction of the fetal ductus arteriosus, nifedipine, 
hypotension.  
  
8. 
Preterm labor can be induced by the intervention or by PPROM. Prophylactic 
tocolysis (first line indomethacin, Magnesium sulfate or nifedipine for 
breakthrough) will be given at the time of the procedure.  The risk for patients 
going into labor without PPROM or infection is less than 2%.  
  
  
  
9. 
Chorioamnionitis- inflammation of the fetal membranes (amnion and chorion) 
due to a bacterial infection. Any invasive procedure may lead to intra-uterine 
infection, despite the procedure being performed in aseptic conditions and the 
prophylactic use of antibiotics. The most frequent cause of chorio-amnionitis is 
PPROM with ascending infection, and its presence requires immediate delivery.  
  
10. 
Placental abruption- very rarely occurs during intrauterine surgery.  
  

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11. 
Amniotic fluid embolism has never been reported during open or fetoscopic 
surgery.  
  
12. 
Maternal death due to fetoscopic procedures has not been reported, and while it 
remains a theoretical possibility, and will be included as a potential outcome in 
the counseling and consent process, the chances are very small. Intensive intra- 
and postoperative monitoring by experienced obstetric anesthesiologists and 
perinatologists should allow for early diagnosis and prompt management of such 
complications as placental abruption, chorio-amnionitis, and amniotic fluid 
embolism.  
  
13. 
Preterm delivery, very preterm delivery, or miscarriage can be induced by the 
intervention or by PPROM.  
  
14. 
Procedure failure and/or inability to complete the procedure fetoscopically 
(resulting in the need for open hysterotomy).  The main risk associated with open 
hysterotomy is uterine dehiscence and rupture in the present pregnancy and 
subsequent pregnancies. Therefore, those patients who undergo open fetal 
surgeries with hysterotomy need special prenatal care and must deliver by 
cesarean section at a maximum of 37 weeks of gestation during the pregnancy. 
After open fetal surgery, patient must wait for 2 years before getting pregnant 
again and must have cesarean section deliveries at a maximum of 37 weeks 
gestation in subsequent pregnancies. In addition, open fetal surgeries with 
hysterotomy are associated with increased risk of premature rupture of the 
membranes and prematurity.  
  
15. 
Pulmonary edema  
  
16. 
Subsequent infertility  
  
  
  
  
1.5.2.2 Anticipated Fetal and Neonate Risks  
  
1. 
Preterm premature rupture of the membranes. In the absence of signs of infection, 
the patients will be managed expectantly with hospitalization, antibiotics and 
possible tocolysis. If there is evidence of infection then delivery will be expedited.  
  
2. 
Preterm birth  
  
3. 
Placental abruption- very rarely occurs during intrauterine surgery.  
  
4. 
Chorioamniotic separation  
  

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5. 
Chorioamnionitis- inflammation of the fetal membranes (amnion and chorion) 
due to a bacterial infection. Any invasive procedure may lead to intra-uterine 
infection, despite the procedure being performed in aseptic conditions and the 
prophylactic use of antibiotics. The most frequent cause of chorio-amnionitis is 
PPROM with ascending infection, and its presence requires immediate delivery.  
  
6. 
Potential sequelae are PPROM, amniotic band syndrome, and umbilical cord 
occlusion with either fetal growth retardation or death.  
  
7. 
Indomethacin (if prolonged use, higher than 72 hours) can be associated with 
significant narrowing of the ductus arteriosus in late gestation. If narrowing 
occurs, indomethacin will be discontinued. However, indomethacin will be used 
for 48 hours maximum.  
  
8. 
Oligohydramnios (decreased amount of amniotic fluid)  
  
9. 
Anesthesia risks for the fetus include fetal bradycardia and fetal demise. In order 
to avoid fetal demise, we will monitor the fetal heart function continuously during 
the entire fetal surgery by a specialized fetal cardiologist.  
  
10. 
No response to the surgical treatment, or failure to reverse the hindbrain 
herniation  
  
11. 
Injury to the fetus from the procedure including organ damage caused by the 
exposure to CO2 gas  
  
12. 
Cord tethering (tissue attachments that limit the movement of the spinal cord 
within the spinal column) which may require later surgery intervention  
  
13. 
The risk for spontaneous intrauterine death after fetoscopy is NOT increased 
compared to the risk of spontaneous death in cases managed by the usual standard 
of care.  
  
14. 
Risks of the dural patch include:  
a. Hematoma formation (a collection of blood in the area of the patch)  
b. Rejection of the patch by the infant’s body (as a foreign material)  
c. Inflammation  
d. Calcification (hardening of the patch)  
e. Delayed bleeding / hemorrhage  
f. Adhesion formation (patch causes tissues to adhere together)  
  
15. 
Complications arising from preterm birth:  
a. Intraventricular hemorrhage (bleeding in the brain)  
b. Retinopathy of prematurity (damage to the infant eyes)  

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c. Sepsis (severe infection)  
d. Necrotizing enterocolitis (damage to the bowel)  
  
1.5.3 Risk Minimizing Procedures and Activities  
1.5.3.1 Fetus  
The fetal procedures will be performed by specialists in fetal medicine and neurosurgery. The 
fetal medicine investigators have extensive experience in fetoscopy. The neurosurgery 
collaborator has significant experience in postnatal and fetal repair of MMC, and is 
experienced in the postnatal care of a baby with MMC. This project will be carried out with 
the help of our fetal intervention, pediatric surgery, neurosurgery and neurology colleagues.  
  
1.5.3.2 Maternal  
Maternal infectious complications: prophylactic administration of intravenous antibiotics. 
Complications and side-effects of epidural analgesia (if applied): the procedure will be 
carried out or under the direct supervision of an expert in this procedure. Preterm labor 
induced by the intervention: prophylactic administration of tocolytics. Maternal 
uterine/placental bleeding: ultrasound guidance of trocar insertion, placement of sutures 
around trocar ports and direct vision and ability to suture bleeding ports because of the 
exposed uterus.  
  
1.5.3.3 Confidentiality  
We will take all precautions to minimize this risk. Once the consent form is signed subjects 
will be assigned a study ID # and will be identified by this ID # throughout the study. All 
data collected will be coded with this study ID # and will be stored on a secure server at 
Mayo Clinic and will be password protected. Only the Principal Investigator, Co- 
Investigators, and designated research staff will have access to the link between the study ID 
and subject identifying information. Any hard copy/paper documentation will be stored in a 
secured area only accessible by designated research staff.  
  
  
1.5.4 Risk/Benefit Analysis  
  
Since we are testing the feasibility of the procedure, there is no current data regarding 
procedure failure. This information will be evaluated. If the procedure is not possible to be 
performed, an open fetal surgical repair will be performed immediately following the 
confirmation of the investigational procedure failure using the same maternal-fetal 
anesthesia. It should be noted that these risks all occur with the current standard open 
procedure as well.  
  
Even with the inherent risks of surgery, the anticipated benefits of significantly increasing 
neonatal outcomes and decreasing neonatal and maternal morbidity, outweigh the risks. The 

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potential benefits to be gained by the subject as a result of participating in this research study 
could be:  
  
1. 
The ability to intervene in neural tube defect repair at an earlier gestational age.  
  
2. 
Decreased neonatal morbidity as a result of reduction of the deleterious intrauterine 
effects of the spina bifida defect through prevention of CSF loss and nerve exposure 
during intrauterine life, thus preserving functional ability.  
  
3. 
Direct improvement of neonatal outcomes by reducing rates of premature delivery 
related to the highly invasive nature of the current model of open uterine fetal 
surgery.  
  
4. 
Direct reduction of maternal morbidity because of shorter hospitalization and 
decreased rates of uterine rupture and uterine dehiscence.  
  
5. 
Decreased future morbidity for mothers by eliminating the need for repeat cesarean 
section and the risk of ruptured uterus in any future pregnancy  
  
The risk to benefit ratio is favorable. A potential benefit to society is the development of 
minimally invasive techniques and equipment that has the potential to change the face of 
fetal therapy for indications other than open neural tube defects.  
1.6  Anticipated Duration of the Clinical Investigation  
  
The investigation is anticipated to take 5 years to enroll the patients to accomplish the 
objectives of the present study. At Mayo Clinic, Rochester we evaluate approximately 5 to 10 
patients per year, and we perform 3-5 procedures per year. We will approach the patients 
about the present study after multidisciplinary evaluation at our Fetal Center and after the 
patients elect to proceed with fetal intervention. Then, we will discuss with the patients the 
present protocol and will offer them the choice to participate. If they consent for the present 
study, we will perform the fetal surgery and will have the Maternal-Fetal Medicine group 
following them until delivery.      
  
  
2 Study Objectives  
  
The primary objective is to evaluate maternal, obstetrical and perinatal outcomes after 
fetoscopic repair of spina bifida.  
  
This is a pilot study to determine the feasibility of performing the minimally invasive 
technique in our institution. The choice of 15 subjects is generally consistent with the 
requirement to evaluate the feasibility of a fetal procedure. If the present study shows that the 
technique is feasible, then the next step will be to perform a randomized controlled study 
comparing the efficacy of the technique and open fetal surgical repair of MMC.  

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2.1 Primary Objective  
  
The primary objective is to evaluate maternal, obstetrical and perinatal outcomes after 
fetoscopic repair of spina bifida.  
  
Our hypothesis is that this minimally invasive technique is feasible, and that this approach 
may have the same efficacy as open fetal surgery for MMC, but with significantly less 
maternal-fetal risk and complications. Both mother and baby will benefit from the surgery. 
The fetus will have a repaired MMC defect, and the mother will not have a uterine incision. 
A hysterotomy increases the risk of uterine rupture and requires that all subsequent deliveries 
are by cesarean section (increasing her risk in all future pregnancies). There is also a 
decreased risk of PPROM and prematurity. Finally, a vaginal delivery is possible following 
the fetal surgery if the baby is shown to have a skin covered repair.  
  
2.2 Secondary Objective  
We aim to evaluate postnatal outcomes.  
  
3 Study Design  
3.1  General Design  
This pilot study is an un-blinded, non-randomized, single arm Pilot Study, which will be 
conducted at Mayo Clinic, Rochester, Minnesota.  
  
All procedures will be performed using the same technique, instruments and materials by the 
same team of people. The minimally invasive technique will be offered to patients carrying 
fetuses with MMC that meet the inclusion criteria, similarly as those currently in place for 
open fetal surgical MMC repair in a similar manner to the MOMs trial.[(18) Adzick NS 2011]  
  
Patients will be offered the minimally invasive technique as an option to the open fetal 
surgical repair of MMC (considered the gold standard). All patients will be closely followed 
up after the procedure, with weekly ultrasound examinations and consultations.  Delivery 
will be scheduled at the participating center hospital and the infants will be followed-up for 
24 months by our research team.  
  
  
3.2  Primary Study Endpoints  
The primary outcome measure will be to evaluate maternal, obstetrical and perinatal 
outcomes after fetoscopic repair of spina bifida progression to a larger study.    
  
To assess and describe the following neonatal outcomes following MMC fetoscopic repair:  
• 
Rate of persistence of CSF leakage from the repaired wound or delayed 
pseudomeningocele formation  
• 
Rate of need for shunt placement in the first year of life  

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• 
Rate of delayed spinal cord tethering at 0-60 months  
• 
Gestational age at delivery  
• 
Long term neurological outcome until 60 months  
• 
Hindbrain herniation  
  
To assess and describe the following maternal outcomes following minimally invasive 
procedure:  
• 
Short term morbidity including preterm labor, preterm premature rupture of 
membranes, placental abruption, and abdominal or vaginal bleeding  
• 
Peri-operative complications such as anesthesia complications, edema, wound 
infection  
• 
Incidence of maternal and obstetrical complications such as oligohydramnios, preterm 
premature rupture of the membranes, prematurity (<37 weeks), extreme preterm birth 
(<32 weeks) and comparison to historical controls and our own open fetal surgery 
cases  
  
3.3  Secondary Study Endpoints  
Secondary endpoints are related to postnatal outcomes including:  
• 
Successful closure of the spina bifida defect (defined as whether the minimally 
invasive technique can be technically performed in human patients (success of 
primary skin closure) by assessing the CSF leakage through the surgical closed defect 
during 24 hours after birth).  
• 
Frequency of reversal of Chiari malformation  
• 
Presence of clinical hydrocephalus that needs postnatal treatment including 
ventriculo-peritoneal shunting or endoscopic third ventriculostomy evaluated until the 
age of 5 years.  
• 
Neurological function evaluated by the lower extremity movements as well as bladder 
and bowel continence.  
• 
In addition the procedure will be assessed as to whether it prevents loss of functional 
neurological level during intra-uterine life by fetal lower extremity movements.   
  
  
  
4 Subject Selection, Enrollment and Withdrawal  
  
Patients with a baby that has been diagnosed with a MMC and fits the criteria, neural tube 
defect repair via the investigational fetoscopic repair procedure will be offered at Mayo 
Clinic, Rochester, MN. The PI and co-investigator fetal surgeons will be the primary contacts 
and the team who will make the initial assessment of whether the patient is a candidate or 
not. Patients will be referred to our center from their primary physician anywhere in the 
country. We will be contacted by the referring physicians to determine whether the patient is 
a suitable candidate. If this is determined to be the case (after discussion with the referring 
physician) the patient will be contacted and the proposed surgery and our study will be 

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discussed. If the patient agrees to participate after full disclosure of the requirements for the 
study and postoperative care she will undergo a detailed ultrasound assessment performed by 
the PI or co-investigator fetal surgeons, each of whom is trained to perform the assessment. 
If, after ultrasound and physical examination, the patient still fits all of the criteria, she will 
be offered the surgery. Patients who meet the eligibility criteria will be extensively 
counseled, and those who wish to participate will provide written informed consent for the 
study.  
  
Sample Size  
This pilot clinical trial will only consist of one group and blinding will not occur. 
Empirically, 15 subjects will provide sufficient power for us to determine the feasibility of 
the technique and a comparison group with which to compare against our patients who have 
had open fetal surgery for neural tube repair.  
  
Fifteen pregnant women with a fetus diagnosed with MMC that fits the criteria are eligible. 
All ethnicities are eligible. Inclusion and exclusion criterion are as follows:  
  
4.1  Inclusion Criteria  
• 
Pregnant women - maternal age 18 years or older  
• 
Gestational age at the time of the procedure between 19 0/7 weeks and 25 6/7 weeks  
• 
Singleton pregnancy.  
• 
MMC diagnosis with the upper boundary located between Thoracic 1 (T1) and Sacral 
1 (S1).  
• 
Evidence of hindbrain herniation (confirmed on MRI to have an Arnold-Chiari type II 
malformation).  
• 
Absence of chromosomal abnormalities and associated anomalies.  
• 
Normal karyotype and/or normal chromosomal microarray (CMA) by invasive testing 
(amniocentesis or CVS). If there is a balanced translocation with normal CMA with 
no other anomalies the candidate can be included.   
• 
Family has considered and declined the option of termination of the pregnancy at less 
than 24 weeks.  
• 
Family meets psychosocial criteria (sufficient social support, ability to understand 
requirements for this study).  
• 
Pregnant subject capable of consenting for their own participation in this study.  
• 
Willingness to undergo an open MMC repair, if necessary  
• 
Parental/guardian permission (informed consent) for follow up of child after birth.  
  
4.2  Exclusion Criteria  
• 
Fetal anomaly unrelated to MMC.  
• 
Multiple gestation  
• 
Declined invasive testing for karyotype (amniocentesis or CVS)  

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• 
Severe kyphosis (defined as curvature of the spina (vertebras) higher than 30o degree 
measured by ultrasonography or magnetic resonance imaging).  
• 
Increased risk for preterm labor including short cervical length (<2.0 cm), history of 
incompetent cervix with or without cerclage, and previous preterm birth.  
• 
Placental abnormalities (previa, abruption, accreta) known at time of enrollment.  
• 
A body-mass index ≥40 at first prenatal visit.  
• 
Contraindications to surgery including previous hysterotomy (whether from a 
previous classical cesarean, uterine anomaly such as an arcuate or bicornuate uterus, 
major myomectomy resection, or previous fetal surgery) in active uterine segment.  
• 
Technical limitations precluding fetoscopic surgery, such as uterine fibroids, fetal 
membrane separation, uterine anomalies incompatible with fetoscopy.  
• 
Amniotic Fluid Index (AFI) < 6 cm if deemed to be due to fetal anomaly, poor 
placental perfusion or function, or membrane rupture. Low amniotic fluid volume that 
responds to maternal hydration is not an exclusion.  
• 
Maternal-fetal Rh isoimmunization, Kell sensitization or neonatal alloimmune 
thrombocytopenia affecting the current pregnancy.  
• 
Maternal HIV, Hepatitis-B, Hepatitis-C status positive because of the increased risk 
of transmission to the fetus during maternal-fetal surgery. If the patients HIV or 
Hepatitis status is unknown, the patient must be tested and found to have negative 
results before enrollment.  
• 
Maternal medical condition that is a contraindication to surgery or anesthesia.  
• 
Patient does not meet other psychosocial criteria, as determined by the psychosocial 
interviewer using a standardized assessment, to handle the implications of the 
trial.Maternal hypersensitivity to collagen  
• 
Patient does not have a support person (i.e. Spouse, partner, mother) available to 
support the patient for the duration of the pregnancy.  
• 
Inability to comply with the travel and follow-up requirements of the trial.  
• 
Participation in another intervention study that influences maternal and fetal 
morbidity and mortality or participation in this trial in a previous pregnancy.  
  
  
  
  
  
4.3  Subject Recruitment, Screening and Enrollment  
  
Recruitment and Selection  
  
Patients identified at or referred to Mayo Clinic, who agree to come to Rochester, Minnesota 
for standard of care evaluation during the study period, and are found upon review of their 
standard of care medical records to be appropriate candidates for the study will be 
approached for entry into the trial.  
  

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The PI will serve as the primary contact. Since patients are being referred by their primary 
physicians, the PI will contact the referring physicians to help determine if the patient is a 
suitable candidate for open fetal surgery of MMC. Patients with fetuses that have diagnosis 
of MMC that meets the inclusion criteria of the study will be offered open fetal surgery as 
part of the prenatal standard. Once the patients elect to proceed with open fetal surgical repair 
of MMC, the fetoscopic repair of MMC will be offered as an investigational procedure and 
the patients will be invited to participate in the present project.  
  
Patients will be extensively counseled about the risks and potential benefits of the 
procedures, as well as the experimental nature of the procedure. They will be also fully 
counseled about the potential for procedure failure with the fetoscopic approach and the need 
for converting to open fetal surgery.   
  
In order to prevent coercion, the investigational procedure will be presented to the patient in a 
manner that is an option and voluntary, if the patient chooses not to participate in the 
investigational procedure, her clinical care will not be affected. After extensive counseling, 
the patients who wish to participate voluntarily in the present study will be asked to provide 
written informed consent. By providing signature on the consent form the patient is 
authorizing participation of her child in this study.  
  
Inclusion of Women and Minorities  
All pregnant women, of any race or ethnicity, evaluated at a Mayo Clinic location with a 
confirmed fetal diagnosis of MMC will be approached for participation in this study.  
  
4.4  Early Withdrawal of Subjects  
4.4.1 When and How to Withdraw Subjects  
  
Patients will be withdrawn from the present study if one of the following conditions happens:  
• 
If the Sponsor-Investigator decides is in the participant(s) best interest.  
• 
Failure of subject to adhere to protocol (surgery) requirements.   
• 
Subject decision to withdraw from the study (withdrawal of consent).  
  
  
  
4.4.2 Data Collection and Follow-up for Withdrawn Subjects  
  
Data collection and follow-up for withdrawn subjects will follow the FDA Guidance  
Document, “Guidance for Sponsors, Clinical Investigators and IRBs – Data Retention When  
Subjects Withdraw from FDA-Regulated Clinical Trials –  
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126489.pdf  
  
  

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• 
the data collected on the subject to the point of withdrawal remains part of the study 
database and may not be removed;  
• 
An investigator may ask a subject who is withdrawing whether the subject wishes to 
provide continued follow-up and further data collection subsequent to their 
withdrawal from the interventional portion of the study. Under this circumstance, the 
discussion with the subject would distinguish between study-related interventions and 
continued follow-up of associated clinical outcome information, such as medical 
course or laboratory results obtained through non-invasive chart review, and address 
the maintenance of privacy and confidentiality of the subject’s information  
• 
If a subject withdraws from the interventional portion of the study, but agrees to 
continued follow-up of associated clinical outcome information as described in the 
previous bullet, the investigator must obtain the subject’s informed consent for this 
limited participation in the study (assuming such a situation was not described in the 
original informed consent form). In accordance with FDA regulations, IRB approval 
of informed consent documents would be required (21 CFR 50.25, 56.109(b), 312.60, 
312.66, 812.100)  
• 
If a subject withdraws from the interventional portion of a study and does not consent 
to continued follow-up of associated clinical outcome information, the investigator 
must not access for purposes related to the study the subject’s medical record or other 
confidential records requiring the subject’s consent. However, an investigator may 
review study data related to the subject collected prior to the subject’s withdrawal 
from the study, and may consult public records, such as those establishing survival 
status.  
  
  
  
  
5 Study Devices  
Devices used in this investigation are either approved or cleared by the FDA for the intended 
use or another specified use.  This study will not be specifically testing the safety or 
effectiveness of any particular device.  The primary objective of this study is to investigate 
the feasibility of performing this minimally invasive procedure with acceptable maternal, 
fetal and neonatal outcomes.  
  
Specific individual device information has been submitted to the FDA under the IDE for 
which this study is being conducted under.  This information will be maintained with the 
FDA and updated as necessary for this study.  
5.1  Preparation of Investigational Devices  
Devices used in the surgical procedure will be prepared according to standard institutional 
practice.  
  

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5.2  Packaging and Labeling  
Devices to be used in the investigational procedure will be identified and labeled as such. The 
following is an example of the label to be used to identify these devices.  
“CAUTION – Investigational Device. Limited by Federal (or United States) law to 
investigational use”   
  
5.3  Receiving, Storage, Distribution and Return  
5.3.1 Receipt of Investigational Devices  
Since the devices to be used in this study are approved marketed devices they will be 
obtained through normal supply chain procedures.  
  
5.3.2 Storage  
Devices will be stored in the original packaging until use.  Any devices designed for multiple 
uses will be disinfected, cleaned and sterilized prior to subsequent use and remain in the 
sterile packaging until use according to standard institutional procedures.  
  
5.3.3 Device Accountability  
Investigational devices will be maintained in the restricted access surgical areas.  At routine 
intervals and at the completion of the study, there will be a reconciliation of devices shipped, 
devices utilized, and devices remaining.  This reconciliation will be logged on the Device 
Accountability form, signed and dated.  Any discrepancies noted will be documented, the 
sponsor-investigator will be notified and an investigation will be conducted to determine the 
cause of the discrepancy.  Devices destroyed on site will be documented in the study files.  
 
  
6 Study Procedures  
6.1  Visit 1 – Screening Visit  
The following routine clinical information will be obtained or collected in the Screening Visit 
as standard of care:  
  
• 
Demographics/Medical History  
• 
Maternal obstetrical history  
• 
Physical Exam including Vital Signs  
• 
Height & Weight  
• 
Laboratory tests –karyotyping  
• 
HIV & Hepatitis B & C testing if not done clinically already.  
• 
Prior/concomitant medications  
• 
Comprehensive obstetrical ultrasound examination, including documentation of 
cervical length, gestational age, biometry, confirmation of Arnold-Chiari II 

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malformation and spina bifida defect, and determination of the anatomic spina bifida 
lesion level as well as the functional lesion level  
• 
Maternal/Fetal MRI to confirm the diagnosis of MMC, spina bifida defect level and 
the presence of Arnold-Chiari II malformation  
• 
Fetal Echocardiogram to rule out structural abnormalities;  
• 
Patient Education including: MMC description, prenatal and neonatal development, 
general expected outcomes and management options  
• 
Clearance for surgery by anesthesia and the obstetrical staff  
• 
Psychosocial evaluation to identify family support and possible confounding social 
issues  
• 
MMC counseling (including information regarding prenatal and postnatal surgery, 
management following prenatal surgery  
  
The standard management options of postnatal repair and open fetal surgical repair will be 
offered to all patients as the first set of therapeutic options and the gold standard. In addition, 
our group will offer the procedure as an alternative experimental option, with a full 
explanation of the experimental nature of the procedure, the technical benefits and 
difficulties, and the risks and potential benefits of the procedure and the limited long term 
outcomes information.  
  
Those patients who request participation in the present study will be informed that they can, a 
priori, select a cross-over arm if for any reason the fetoscopic procedure is not possible. They 
can elect that an open fetal surgical repair of MMC be performed (if MOMs criteria are met) 
or postnatal intervention. This would allow her to have a significantly less morbid procedure 
on the uterus than open hysterotomy. In the event that this is not possible an open uterus 
procedure can be performed. In addition, a standardized packet of information will be 
provided. This packet contains materials describing MMC and includes materials describing 
prenatal and neonatal development, general outcomes expected, and management options in 
pregnancy and the newborn period.  
6.2  Visit 2 – Fetoscopic Procedure to Repair MMC  
The procedure will be performed between 19 0/7 and 25 6/7 weeks at the Mayo Clinic, 
Jacobson Building, Rochester, Minnesota.  
  
Maternal-Fetal anesthesia:  
This procedure will be performed under general anesthesia with placement of a maternal 
epidural catheter for postnatal analgesia management. This is the same anesthesia approach 
currently in use for open fetal surgeries. The rationale for using the same anesthetic technique 
for this minimally invasive procedure and for open fetal surgical repair of MMC is to allow 
moving to open fetal surgery in those cases where the fetoscopic procedure cannot be 
performed. This will also provide adequate fetal anesthesia during the procedure.  
  
Prophylactic Tocolysis and antibiotics:  
Prophylactic tocolysis will be used in all patients with a protocol employing indomethacin 
25mg Q6 for 24 hours and nifedipine 10 mg Q6 for 24 hours. If regular, significant, uterine 

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contractions are observed, therapeutic tocolysis will be started with magnesium sulfate – 6 
gram IV loading dose followed by a 2 gram/hour continuous infusion. Prophylactic 
antibiotics will also be used during the procedure using Cephalexin 1 g IV immediately 
before the procedure. Nafcillin will be injected into the amniotic cavity at the conclusion of 
the procedure. Steroids for lung maturity: steroids for fetal lung maturation will be given 
between 24 and 25 6/7 weeks (two doses of 12 mg betamethasonegiven 24 hours apart, with 
the last dose given 48-72 hours before the procedure.  
  
Minimally invasive procedure:  
We will use a standard laparotomy approach that we currently use in our open fetal surgeries. 
This involves a transverse lower abdominal skin incision and exposure of the rectus sheath 
with entry into the abdomen through a vertical or horizontal fascial incision. Once the 
maternal belly is opened the uterus is exposed and ultrasound is performed to determine the 
position of the fetus. If necessary, the uterus will be exteriorized and the fetus will be gently 
repositioned using external version techniques under ultrasound guidance in order to have the 
fetal back facing upwards (when the mother is supine). A small volume of amniotic fluid (+/- 
200cc) will be withdrawn through an 18G needle (placed under ultrasound guidance) prior to 
starting the fetoscopic portion of the surgery, and the amniotic fluid will be replaced with 
carbon dioxide gas at a pressure of less than 20 mmHg. A 9-12 Fr (Cook Medical, Inc., 
Indiana, USA) or Step™ Short 5 mm (Covidien, Massachusetts, USA) cannula will be 
introduced into the amniotic cavity by Seldinger technique under ultrasound guidance, and 
sutured in place with a through and through vicryl stitch that will plicate the fetal membranes 
and prevent extension of membrane separation.  
The pediatric cystoscope (Karl Storz, Tuttlingen, Germany or Richard Wolf Medical  
Instruments Corp, Illinois, USA) will be placed into the uterus via this port. An additional 
610F port will be added under vision and sutured in place as described. The Storz 
instruments (graspers, scissors, and needle drivers) will be used via these ports to perform the 
surgery. If necessary additional amniotic fluid will be removed under direct vision and 
replaced by carbon dioxide at the lowest pressure that will enable adequate visualization of 
the defect and surrounding skin (< 20mmHg). The maximum insufflation pressures used by 
Kohl et al ranged from 9 mmHg to 25 mmHg with a median of 17 mmHg). The fetus will be 
“floating” in the amniotic fluid with the spina bifida lesion exposed to the gas medium. A 
humidifier (Insuflow, Lexion Medical LLC, St. Paul, Minnesota, USA) will be used during 
the fetoscopic procedure in order to maintain the chorion-amniotic membranes intact and 
wet. Because of the unique circumstances of the laparotomy and exteriorized uterus, the 
access ports can be placed distant from the placenta in order to minimize the chances of 
abruption of the placenta.  
  
The meningomyelocele sac will be opened at the interface of skin and membranes with the 
micro scissors to free the placode from the membranes circumferentially. The placode will be 
allowed to descend into the lesion leaving the skin edge above. A piece of dural substitute 
material (Medtronic Durepair regeneration matrix, Medtronic, Oakland, NJ, USA) will be cut 
to the size of the meningomyelocele defect, introduced through a port using a grasper and 
laid on top of the placode without any suture. The main reason for placing a piece of dural 

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substitute material over the placode is to thicken the repair and prevent cord tethering and 
CSF leakage. The skin edges will be primarily opposed and sutured together using standard 
surgical technique with barbed 4/0 (Covidien,V-loc or Ethicon Stratfix) suture. If skin 
closure is not possible using the available skin, relaxing incisions will be made using micro 
scissors 1-2cm lateral to the defect to allow a primary skin closure. If primary skin closure is 
not possible after relaxing incisions are made, the uterus will be opened and the procedure 
completed with a sewn in patch of AlloDerm (Life Cell Corp. Branchburg, NJ)  using an 
open technique.  
  
Before removing the trocar, the gas will be removed through the port and the amniotic fluid 
will be replaced by lactated ringer.  
  
6.3  Weekly postsurgical visits – Postsurgical Management before delivery (V3 follow-ups)  
The expected hospital course is 96 hours; however, it is possible that the patient will be 
hospitalized for complications or preterm labor. The patient will then be discharged to nearby 
accommodation for long term stay until delivery (usually Ronald McDonald House in 
Rochester, Minnesota) Patients will be on modified bed rest for the first 2 weeks post 
discharge, but will subsequently be allowed to graduate to moderate activity if the uterus is 
quiescent.  
  
Patients will return on a weekly basis for fetal ultrasound examinations and consultations. 
Targeted ultrasonography will be used to evaluate the functional neurological level (as shown 
by lower extremity motility), the posterior ventricles, the Arnold-Chiari II malformation, 
amniotic fluid level, & membrane status (weekly). Fetal Surveillance by biophysical profiles 
and Doppler studies will begin at 34 weeks In addition a monthly comprehensive ultrasound 
examination will be performed and an MRI will be repeated at 30-32 weeks of gestation.  
  
  
  
  
6.4  Delivery (V4)  
If MRI at 30-32 weeks shows that skin is covering the defect, and that there has been reversal 
of the Chiari malformation, the patient will be delivered according to obstetric principles 
which include the option of a vaginal delivery. Cesarean section will only be performed 
based on obstetrical need. This is a major benefit of the fetoscopic procedure, and has long 
standing implications for the obstetric future of the mother. Not only will she avoid the risk 
of uterine rupture in the current pregnancy, but she potentially a cesarean section for the 
delivery of the current baby and for all subsequent pregnancies. This will lower her risk of 
hemorrhage and death in the current pregnancy, and will decrease her risk of placenta accreta 
in subsequent pregnancies.  
  

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6.5  Postnatal Follow-up Visit (V5)  
  
The infants will be followed-up by the pediatric neurosurgery service. At birth, a physical 
examination of the child will be performed to evaluate the spine, the spina bifida defect and 
the need for postnatal MMC surgical repair. In addition, cranial ultrasound will be performed 
in order to evaluate the baby for evidence of ventriculomegaly, presence of hydrocephalus 
and an Arnold- Chiari II malformation.  
The following information will be collected between birth and discharge:  
• 
Physical Exam – Evaluate spine, the spina bifida defect and need for postnatal MMC 
repair  
• 
Urologic Assessments – ultrasound of the urinary tract and voiding cystourethrogram 
(VCUG)  
• 
Cranial Ultrasound – Evaluate for evidence of ventriculomegaly presence of 
hydrocephalus and Arnold-Chiari II malformation  
If there is progressive hydrocephalus, the infant will be treated by pediatric neurosurgery with 
either a shunt or endoscopic third ventriculostomy. We will also perform motor examination 
of the legs and anal sphincter response.  
  
6.6  Long-Term Follow-Up, 12 Months of Age (V6)  
  
Infants will be monitored clinically for hydrocephalus at 3-month intervals for the first year.  
At 12 months of age, all children will be evaluated with physical, urologic and neurologic 
examinations as well as routine developmental testing as is standard for babies with postnatal 
spina bifida repair. The 12-month examination will include urodynamic test, imaging of the 
spine to determine the anatomical level of the lesion and magnetic resonance imaging of the 
head and spine.  
• 
Urologic Assessments – ultrasound of the urinary tract at 3-month intervals for the first 
year and urodynamic testing at 3 and 12 months of age  
• 
Developmental Testing – Bayley Scales of Infant and Toddler Development™ (3rd 
edition) Screening Test  
• 
MRI of head and spine  
  
• 
Cranial Ultrasound – obtain at 3-month intervals for the first year and at 12 months of age  
6.7  Long-Term Follow-Up, 60 Months of Age End of Study (V7-V10)  
  
  
All children will be evaluated at 24, 36, 48 and 60 months of age with physical and 
neurologic examinations. Additional assessments will be completed at each visit as specified 
below:  
  
Visit 7 (24 months of age):   
• 
Urologic Assessment - ultrasound of the urinary tract  

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• 
Developmental Testing - Bayley Scales of Infant and Toddler Development™ (3rd 
edition) Full Test  
 
Visit 8 (36 months of age):  
• 
Urologic Assessments – ultrasound of urinary track and urodynamic testing  
• 
Developmental Testing - Bayley Scales of Infant and Toddler Development™ (3rd 
edition) Full Test  
 
Visit 9 (48 months of age):  
• 
Urologic Assessment - ultrasound of the urinary tract  
• 
MRI of head and spine  
  
Visit 10 (60 months of age):  
• 
Urologic Assessments – ultrasound of the urinary tract an urodynamic testing  
• 
MRI of head and spine  
  
The study will conclude at the 60-month visit and in those cases where the patient does not 
return to Mayo Clinic for the clinical follow-up visits, we will request the medical records 
from the institution that the patient was seen at and collect the follow-up data from the 
medical records. All patients will be asked to sign a medical record release to allow this to 
occur.  
  
6.8  Unscheduled Visits  
  
Pregnant women who have undergone fetoscopic repair of MMC and have any complications 
such as preterm contractions, PPROM, signs of infection, vaginal bleeding will be treated as 
usual standard clinical care. Additional unscheduled visits will be performed depending on 
maternal symptoms and signs as part of the standard prenatal care. Any required emergency 
or unscheduled care will be treated by staff at Mayo Clinic.  All visits will be recorded.  
  
  
  
6.9  Schedule of Events Table  
  
  
V1  
V2  
V3  
V4  
V5  
V6  
V7  
V8  
V9  
V10  
Study Activity  
Screening  
MMC 
Feto-  
scopic 
surgery  
Weekly 
PostSurgical  
Visits  
Delivery  Postnatal  
Follow  
Up  
12 Mo. 
of age   
  
24 Mo. 
of age   
  
36 Mo. 
of age   
48 Mo. 
of age   
60 Mo. 
of age   
Visit Window  
  
  
  
  
  
+/- 2  
months  
+/- 2  
months  
+/- 2  
months  
+/- 2  
months  
+/- 2  
months  
Consent  
X  
  
  
  
  
  
  
  
  
  

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History  
X  
X  
X  
X  
X  
X  
X  
  
  
  
Physical Exam  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Neurologic Exam  
  
  
  
  
X  
X  
X  
X  
X  
X  
Fetoscopic  
Procedure  
  
X  
  
  
  
  
  
  
  
  
Weekly Fetal 
ultrasound  
  
  
X  
  
  
  
  
  
  
  
Case Report Forms  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Weekly Doppler 
Studies  
  
  
X  
  
  
  
  
  
  
  
Urology Follow-
up  
  
  
  
  
X  
X  
X  
X  
X  
X  
Monthly  
Comprehensive  
Ultrasound  
  
  
X  
  
  
  
  
  
  
  
MRI  
  
  
X*  
  
  
X  
 
 
X  
X  
Cranial Ultrasound  
  
  
  
  
X**  
X  
  
  
  
  
Developmental  
Testing  
  
  
  
  
  
X  
X  
X  
  
  
Concurrent  
Medications  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Adverse Events  
  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Serious Adverse  
Events  
  
X  
X  
X  
X  
X  
X  
X  
X  
X  
* = at 30-32 weeks only  
** = Hydrocephalus monitoring every 3 months during the first year of life  
  
  
  
7 Statistical Plan  
7.1  Sample Size Determination  
  
This pilot clinical trial will only consist of one group and blinding will not occur. 
Empirically, 15 subjects will provide sufficient power for us to determine the feasibility of 
the technique.  
  
7.2  Statistical Methods  
  
Descriptive Statistics  
  

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Descriptive statistics (e.g., mean standard deviation, median, minimum and maximum for 
numerical data and counts and percents for categorical data) will be calculated, as appropriate 
for all variables. Baseline values for demographic, clinical, and outcome variables (primary 
and secondary) will be described.  
  
All pregnant women/fetuses entered into the study at Visit 1 will be included in the safety 
analysis. The frequencies of AEs by type, body system, severity and relationship to study 
procedures will be summarized. SAEs (if any) will be described in detail.  
AE incidence will be summarized along with the corresponding exact binomial 95% two- 
sided confidence intervals.  
  
Handling of Missing Data  
  
Missing data will be addressed using last observation carry forward (LOCF) where 
appropriate. Where LOCF is not appropriate missing data will be left as missing. Heavy 
tailed distributions and outliers will be addressed by considering transformations to allow 
approximate normality of the means. Data will be reviewed for outliers before analysis and 
values may be checked against source data.  
  
Multiplicity  
  
For both the primary analyses, and the secondary analyses, there will be one primary (or first) 
analysis and thus no correction will be made for multiple comparisons. A sequence of 
outcomes of interest will be described for each analyses, and significance will be assessed in 
the order of these sequences. Therefore, testing involves closed testing procedures that 
protect the probability of falsely rejecting the null hypothesis. If a test fails to be significant, 
then further tests will be calculated in an exploratory rather than inferential manner.  
7.3  Subject Population(s) for Analysis  
  
All subjects who are consented and intended to be treated will be included in the analysis.  
  
  
  
8 Safety Management and Adverse Events  
The initial Safety Outcome criteria will be considered to have been achieved for the planned 
15 subjects if;  
• 
Fewer than one (1) maternal SAE ≥ Grade 4 as defined by CTCAE and determined to 
be “probably” or “definitely” related to the procedure. (Examples: maternal Grade 4 
event such as (i) maternal death as a result of the investigational procedure, (ii) a life 
threatening event (risk of death) as a result of the investigational procedure.)  
  
• 
Fewer than one (1) fetal SAE ≥ Grade 4 as defined by CTCAE and determined to be 
“probably” or “definitely” related to the procedure. (Examples: (i) death as a result of 

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the investigational procedure, (ii) a life-threatening event (risk of death) as a result of 
the investigational procedure.)  
  
• 
Fewer than one (1) obstetrical SAE ≥ Grade 4 as defined by CTCAE and determined 
to be “probably” or “definitely” related to the procedure.  (Examples: obstetrical 
Grade 4 event = premature rupture of the membranes, fetal grade 5 event = placental 
abruption)  
 
• Any clinically indicated MRIs obtained in the interim between study required and 
standard of care MRI intervals will be reported as an adverse event to the IDE. 
 
  
All adverse events occurring during the study, including those not meeting the criteria of an 
Unanticipated Adverse Device Effect (UADE) will be recorded on the appropriate case 
report form.  Records of these events will be maintained and reports submitted to the FDA 
and IRB according to the regulatory requirements.  Expected clinical adverse events and 
nonsignificant (not serious) clinical adverse events will be reported. Expected clinical 
adverse events and anticipated adverse device effects are those listed in Section 1.5.2.  
8.1  Stopping Rules  
  
Trial Stopping Rules: The trial will be voluntarily placed on hold for the following reasons 
until the FDA, Sponsor-Investigator and the DSMB (see Section 8.7.1) evaluate the safety of 
the trial and address any required changes to the investigational plan to decrease risk and 
improve safety:  
• 
if there is one (1) maternal SAE ≥ Grade 4 as defined by CTCAE following the 
investigational procedure, and determined to be  
“probably” or “definitely” related to the procedure  
• 
if there is one (1) fetal SAE ≥ Grade 4 as defined by CTCAE the investigational 
procedure, and determined to be “probably” or “definitely” related to the procedure.  
• 
if there is one (1) obstetrical SAE ≥ Grade 4 as defined by CTCAE the 
investigational procedure, and determined to be “probably” or “definitely” related to 
the procedure.  (Examples: obstetrical Grade 4 event = premature rupture of the 
membranes, fetal grade 5 event = placental abruption)  
  
  
  
8.2  Clinical Adverse Events  
Clinical adverse events (AEs) will be monitored throughout the study.  
8.3  Definition of an Adverse Event  
  
An adverse event is any untoward medical occurrence in a pregnant woman and/or /fetus who 
has received an intervention (drug, biologic, or other intervention).  The occurrence does not 

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necessarily have to have a causal relationship with the treatment. An AE can therefore be any 
unfavorable or unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or 
intervention, whether or not considered related to the medicinal product or intervention.  
  
All AEs (including serious AEs) will be noted in the study records and on the case report 
form with a full description including the nature, date and time of onset, determination of 
non-serious versus serious, intensity (mild, moderate, severe), duration, causality, and 
outcome of the event.  
8.4  Definition of Unanticipated Adverse Device Effect (UADE)  
  
An UADE is any serious adverse effect on health or safety or any life-threatening problem or 
death caused by, or associated with a device, if that effect, problem or death was not 
previously identified in nature, severity, or degree of incidence in the investigational plan or 
application (including supplementary plan or application), or any other unanticipated serious 
problem associated with a device that relates to the rights, safety, or welfare of subjects (21 
CFR 812.3(s)).  
8.5  Definition of a Serious Adverse Event (SAE)  
  
A SAE is any adverse drug or intervention experience that results in any of the following 
outcomes:  
• 
Death as a result of  the Investigational Procedure  
• 
A life-threatening event (at risk of death at the time of the event),  
• 
**Requires inpatient hospitalization or prolongation of existing hospitalization,  
• 
A persistent or significant disability/incapacity, or  
• 
A congenital anomaly/birth defect in the offspring of a pregnant woman related to 
the procedure.  
Important medical events that may result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse event when, based upon appropriate 
medical judgment, they may jeopardize the pregnant woman/fetus and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition.  
  
**For this study, it is recognized that inpatient hospitalizations are not uncommon for 
pregnant women. Standard obstetrical clinical practice generally requires women to be 
hospitalized for observation and fetal monitoring whenever possible symptoms of preterm 
labor, preterm premature rupture of membranes, infection, or any other symptoms related to 
pregnancy may occur. Therefore, every hospitalization incurred by participants in this study 
will not be considered a Serious Adverse Event (SAE). Each hospitalization will be 
individually assessed by the Principal Investigator as to whether the reason for the 
hospitalization meets criteria for a SAE. All pregnancy complications will be collected as 
Adverse Events during this research study.  
  

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A distinction should be drawn between serious and severe AEs. A severe AE is a major event 
of its type. A severe AE does not necessarily need to be considered serious. For example, 
nausea which persists for several hours may be considered severe nausea, but would not be 
an SAE. On the other hand, a stroke that results in only a limited degree of disability may be 
considered a mild stroke, but would be a SAE.  
  
  
8.5.1 Relationship of SAE to study device or other intervention  
  
The relationship of each SAE to the study intervention will be characterized using one of the 
following terms: definitely, probably, possibly, unlikely or unrelated.  
  
Definitely – the event follows in a reasonable temporal sequence from the study intervention 
and the event cannot be explained by the subject’s medical condition or other therapies  
  
Probably – there is temporal relationship between the event and study intervention or the 
relationship is suggestive and the event is unlikely to be explained by the subject’s medical 
condition or other therapies   
  
Possibly – there is some temporal relationship between the event and the study intervention 
and the event is less likely to be explained by the subject’s medical condition or other 
therapies   
  
Unlikely – there may or may not be some temporal relationship between the event and the 
study intervention and the event is more likely to be explained by the subject’s medical 
condition or other therapies   
  
Unrelated – the event is due to an underlying or concurrent illness or effect of a concomitant 
therapy and is not related to study intervention (e.g., there is no temporal relationship to the 
study intervention, or has a much more likely alternative etiology)   
  
  
  
  
8.5.2 Severity of Adverse Events  
  
The sponsor-investigator will use the following NCI CTCAE v5 definitions to grade the 
severity of each AE:  
  
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental ADL*.  

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Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL**.  
Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 
5 Death related to AE.  
  
Activities of Daily Living (ADL)  
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc.  
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden.  
  
8.5.3 Eliciting Adverse Event Information  
Adverse events will be captured through medical record review, self-report, physician 
evaluation, non-directive questioning during study visits, and/or clinical or research tests. 
See Section 1.5.2 for a list of potential maternal and fetal complications as a result of the 
study intervention.  
  
8.5.4 Recording Adverse Events  
The Sponsor-Investigator will promptly review all adverse events and abnormal test findings 
to determine the causality to the investigational product. Expectedness of the adverse event 
will be based on the Sponsor-Investigator’s determination and study documents (i.e. study 
protocol, informed consent, or IDE Application). All AEs (serious and non-serious) will be 
noted in the study records and recorded on the Adverse Event case report form with a full 
description including the nature, date and time of onset, determination of non-serious versus 
serious, intensity/grade, duration, causality, relationship to the investigational product, and 
outcome of the event. Once an adverse event is detected, it will be followed to the extent 
possible until its resolution or until it is judged to be permanent. Any increase in severity of 
an adverse event will be captured as a new event.  
  
SAEs will be documented as specified above and the relationship of each SAE to the study 
intervention will be characterized as outlined in Section 8.5.  The SAEs and UADEs will be 
closely followed and any changes in severity (improving or deteriorating) will be 
documented until resolved.    
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Study subjects will be routinely 
questioned about adverse effects at study visits. Information on all adverse events should be 
recorded immediately in the source document, and also in the appropriate adverse event case 
report form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic, laboratory 
or procedure results should recorded in the source document.  
  
All adverse events occurring during the study period must be recorded.  All observed or 
volunteered adverse effects (serious or non-serious) and abnormal test findings, regardless of 
the treatment group if applicable or suspected causal relationship to the investigational device 

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or if applicable other study treatment or diagnostic product(s) will be recorded in the 
subjects’ case history.  For all adverse effects sufficient information will be pursued and or 
obtained as to permit; an adequate determination of the outcome, an assessment of the casual 
relationship between the adverse effect and the investigational device or, if applicable other 
study treatment or diagnostic product.  The clinical course of each event should be followed 
until resolution, stabilization, or until it has been ultimately determined that the study 
treatment or participation is not the probable cause.  Serious adverse events that are still 
ongoing at the end of the study period must be followed up, to determine the final outcome.  
Any serious adverse event that occurs after the study period and is considered to be at least 
possibly related to the study treatment or study participation should be recorded and reported 
immediately.  
  
Causality and severity assessment  
The sponsor-investigator will promptly review documented adverse effects and abnormal test 
findings to determine 1) if the abnormal test finding should be classified as an adverse effect; 
2) if there is a reasonable possibility that the adverse effect was caused by the investigational 
device or other study treatments; and 3) if the adverse effect meets the criteria for a serious 
adverse effect.  
  
If the sponsor-investigator’s final determination of causality is “unknown and of questionable 
relationship to the investigational device or other study treatments,” the adverse effect will be 
classified as associated with the use of the investigational device or other study treatments for 
reporting purposes.  If the sponsor-investigator’s final determination of causality is 
“unknown but not related to the investigational device or other study treatments,” this 
determination and the rationale for the determination will be documented in the respective 
subject’s case history.  
  
8.6  Adverse Event Reporting  
Unanticipated problems related to the research involving risks to subjects or others that occur 
during the course of this study (including SAEs) will be reported to the IRB in accordance 
with IRB Policies and Procedures for Unanticipated Problems Involving Risks to Subjects or 
Others. AEs that are not serious but that are notable and could involve risks to subjects will 
be summarized in narrative or other format and submitted to the IRB at the time of 
continuing review.  
  
  
8.6.1 
Adverse Event Reporting Period  
  
Detailed information concerning adverse events (AEs) will be collected and evaluated 
throughout the trial. An AE is any event that is serious, deemed related to the study and/or 
unexpected in nature, severity, or frequency, or fits IRB definition of adverse event. 
Reporting of these events will be as follows:  
  

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For any maternal, fetal or neonatal deaths or other life-threatening events associated with the 
study intervention:  
• Promptly complete an Adverse Event Report  
  
Besides maternal, fetal and neonatal deaths, the following are examples of adverse events to 
be reported.  
  
Maternal events: Stroke, drug allergy, uterine rupture, pulmonary embolus, ascites, spinal 
headache from epidural placement, amniotic fluid embolism, hemorrhage that requires blood 
transfusion or laparotomy, chorioamnionitis, pulmonary edema requiring diuretics or 
intubation, complications of general anesthesia, magnesium toxicity, chorioamniotic 
separation, bleeding from the placenta as a result of study intervention and anhydramnios.  
  
8.6.2 IRB Notification of SAEs and Other Unanticipated Problems  
  
This study population is focused fetuses that are affected with MMC. There are multiple 
potential complications that may occur to the pregnant woman and fetus by nature of the 
diagnosis of MMC and interventions associated with the study. These would be expected and 
would not require reporting to the IRB except at continuing review unless they occur at a 
greater than anticipated frequency.  
  
See Section 1.5.2 for a list of potential maternal and fetal complications to the intervention. 
The Investigator will promptly notify the IRB of all Unanticipated, Serious Adverse Events 
that are related to the research activity. Other unanticipated problems related to the research 
involving risk to pregnant women/fetus/children or others will also be reported promptly.  
  
When an adverse event has been identified, the study team will take appropriated action 
necessary to protect the study participant and then complete the Study Adverse Event 
Worksheet and log.  The sponsor-investigator will evaluate the event and determine the 
necessary follow-up and reporting required.  
  
The sponsor-investigator will promptly review documented Unanticipated Adverse Device 
Effects and as necessary shall report the results of such evaluation to FDA within 10 working 
days and Mayo IRB within 5 working days of initial notice of the effect.  Thereafter the 
sponsor-investigator will submit such additional reports concerning the effect as requested.  
  
8.6.3 
Sponsor-Investigator Reporting: Notifying the FDA  
  
The sponsor-investigator will report to the FDA all unanticipated adverse device effects 
according to the required reporting timelines, formats and regulations.  
  
The sponsor-investigator will submit a completed report to the FDA’s Center for Devices and 
Radiological Health for any observed or reported adverse effect that is determined to be an 

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unanticipated adverse device effect.  A copy of this completed form will be provided to the 
DSMB and all participating sub-investigators.  
  
The report will be submitted to the FDA as soon as possible and, in no event, later than 10 
working days after the sponsor-investigator first receives notice of the adverse effect.  
  
If the results of the sponsor-investigator’s follow-up evaluation shows that an adverse effect 
that was initially determined to not constitute an unanticipated adverse device effect does, in 
fact, meet the requirements for reporting; the sponsor-investigator will submit a report as 
soon as possible, but in no event later than 10 working days, after the determination was 
made.  
  
For each submitted report, the sponsor-investigator will identify all previously submitted 
reports that that addressed a similar adverse effect experience and will provide an analysis of 
the significance of newly reported adverse effect in light of any previous, similar report(s).  
  
Subsequent to the initial submission of a report, the sponsor-investigator will submit 
additional information concerning the reported adverse effect as requested by the FDA.  
  
Reporting Process  
  
The contact information for submitting reports is:  
  
Food and Drug Administration  
Center for Devices and Radiological Health Document 
Mail Center - WO66-G609  
10903 New Hampshire Avenue  
Silver Spring, Maryland 20993-0002  
8.6.4 Deviations from the investigational plan.  
The sponsor-investigator shall notify Mayo IRB (see 21 CFR 56.108(a) (3) and (4)) of any 
deviation from the investigational plan to protect the life or physical well-being of a subject 
in an emergency. Such notice shall be given as soon as possible, but in no event later than 5 
working days after the emergency occurred. Except in such an emergency, prior approval by 
the sponsor-investigator is required for changes in or deviations from a plan, and if these 
changes or deviations may affect the scientific soundness of the plan or the rights, safety, or 
welfare of human subjects, FDA and IRB notification in accordance with 21 CFR 812.35(a) 
also is required.  
  
  
8.6.5 
Follow-up Reports  
  
If a SAE has not resolved at the time of the initial report and new information arises that 
changes the investigator’s assessment of the event, a follow-up report including all relevant 
new or reassessed information (e.g., concomitant medication, medical history) will be 

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submitted to the IRB. The investigator will be responsible for ensuring that all SAE are 
followed until either resolved or stable.  
  
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At the 
last scheduled visit, the investigator should instruct each subject to report, to the investigator, 
any subsequent event(s) that the subject, or the subject’s personal physician, believes might 
reasonably be related to participation in this study.   
  
8.6.6 General Physical Examination Findings  
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities that 
meet the definition of an adverse event must also be recorded and documented as an adverse 
event.  
8.7  Medical Monitoring  
It is the responsibility of the sponsor-investigator to oversee the safety of the study.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events 
as noted above, as well as the construction and implementation of a site data and 
safetymonitoring plan (see Section 10 Auditing, Monitoring and Inspecting).  Medical 
monitoring will include a regular assessment of the number and type of serious adverse 
events.  
  
8.7.1 Independent Data and Safety Monitoring Board  
This study will use the currently established independent Department of Surgery Data and Safety 
Monitoring Board (DSMB) which meets quarterly reviewing each study at least bi-annually. Special 
meetings of the DSMB may be convened more often, as necessary, to address urgent concerns 
regarding patient safety and data integrity.  
  
Membership of the DSMB will include those with expertise in the field, experience conducting 
human subjects research and statistical knowledge, independence from direct management of the 
study and an absence of conflict of interest.;  
• 
The chair of the DSMB (voting member), chosen from the physician representatives   
• 
Additional three or more physician representatives (voting members)   
• 
Biostatistician representative (voting member)   
• 
Representative from the Surgical Clinical Research Office (non-voting members)   
• 
Ad hoc members appointed to the committee by the chair when additional expertise is 
required in reviewing certain studies (study-specific non-voting members)   
• 
A quorum is defined as three or more voting members of the committee that must 
include at least one physician and one statistician.  
  
  
Initial Review:   

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The DSMB may meet prior to enrollment of subjects to review the protocol, informed 
consent and the Data Safety Monitoring Plan (DSMP) to determine:   
• 
The study’s risks and benefits and safety of research subjects   
• 
Suggest improving the study design   
• 
Identify what data will be required for review   
• 
Identify early stopping rules   
 All trials are required, when appropriate, to have early stopping rules for toxicity 
and for efficacy. Early stopping rules are required when an intervention of more 
than minimal risk is used. Efficacy is assessed in an interim analysis when such 
analysis can appropriately be obtained as part of the study. Design and 
implementation of the stopping rules are the responsibility of the study principal 
investigator (PI) and the study statistician. The Surgery Peer Reviewed Research 
Committee (SPRRC) is responsible for reviewing the proposed rules and 
approving them, during the standard protocol review process, for submission to 
the Institutional Review Board (IRB). The IRB has the final approval of the study, 
including the stopping rules.   
  
Bi-annual Review:   
• 
Interim data review to detect evidence efficacy or adverse events and determine if the 
study should continue, be modified or be stopped.   
• 
Progress evaluation to assess recruitment and retention of subjects, protocol 
adherence, and data quality/completeness and accrual.   
  
Meeting Timing and Frequency   
The DOS DSMB meets quarterly reviewing each study at least bi-annually. Special meetings 
of the DSMB may be convened more often, as necessary, to address urgent concerns 
regarding patient safety and data integrity.   
  
Studies identified by the IRB for more intensive monitoring may be reviewed on a quarterly, 
rather than semiannual basis. Special sessions of the DSMB may be held to address protocol 
specific issues, as necessary if the events of that protocol require review prior to the next 
scheduled DSMB meeting. Such meetings may occur through an electronic format.   
  
Meeting Agenda and Format   
The Principal Investigator will be notified 4 weeks prior to the scheduled meeting. The 
Principal Investigator will be expected to submit the required reports 2 weeks before the 
meeting.   
  
DSMB members will receive an agenda with information for the studies to be reviewed 
approximately one week prior to DSMB meeting to allow for preliminary study and review. 
The information to be distributed prior to the meeting includes a listing of serious adverse 
events, a copy of IRB annual progress report if submitted since last DSMB review and, if 
available, an interim analysis.   

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• 
Each study is assigned two primary reviewers for review, presentation during the 
DSMB meeting and making a recommendation. The primary reviewers may ask the 
PI for additional information or clarification in advance of the meeting.   
• 
If a Committee member is either a principal investigator or co-principal investigator, 
statistician or other study team member for a study under review, or has any other 
conflict of interest (including substantial financial interest in the study sponsor), that 
member may be present to answer questions regarding the study, but must abstain 
from voting and leave the room prior to final deliberations and voting on that study. If 
the Chair is the principal investigator for the study, another member of the Committee 
oversees the Committee deliberations and voting.   
  
The meeting format may include both a Closed Session and an Open Session as required by 
each protocol.   
  
  
Open Session:  
The DSMB may request the Principal Investigator and/or study team to attend to provided 
clarification or respond to issues. The open session will focus on the conduct and progress of 
the study and review the safety and efficacy data.   
  
Closed Session:   
Only DSMB members should be present at the closed session. In this session the DSMB will 
review the data and evaluate the study:   
• 
conduct ( accrual),   
• 
safety (adverse events) and   
• 
data integrity (eligibility and protocol deviations)   
• 
the risk benefit ratio for trial subjects   
  
Meeting Materials   
DSMB interim report templates will be prepared by the study team and the statistician, for 
review at the DSMB meeting. Interim data reports that summarize the safety data and 
describe the status of the study generally consist of two parts:   
  
Part 1 – Open Session Report   
1. Accrual summary that describes subjects screened, enrolled, completed or withdrawn.   
2. A listing of adverse events and serious adverse events blinded to treatment group.   
3. A copy of the annual Mayo IRB continuing review   
  
Part 2 – Closed Session Report   
This confidential report is generally the same as the open session report but unblinded to 
treatment group. This report may also include data on study outcomes including safety data.   
  
  
  
  

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Meeting Outcomes   
In the closed session the DSMB will vote to take one of the following actions for each 
protocol reviewed and present their recommendation to the Principal Investigator:   
1.Full Approval: enrollment may continue; no outstanding questions regarding adverse 
events or study progress.   
2.Conditional Approval: enrollment may continue with the requirement for 
submission by the principal investigator of a satisfactory response to DSMB 
concerns. If the principal investigator fails to provide a satisfactory response within 
14 days or receives an additional extension beyond this time period, enrollment in the 
study will be suspended.   
3.Suspension: enrollment immediately suspended pending principal investigator 
response to DSMB concerns.   
4.Closure: study closed due to unacceptable adverse event occurrence rate or other 
study issues as deemed appropriate by the DSMB.   
5.The occurrence of events that prompt the activation of the protocol specific early 
stopping rules for pilot, phase II, and phase III studies require prompt review by the 
study team. The study team formulates an appropriate plan of action to ensure patient 
safety (as required by the FDA & IRB). This may include protocol changes and may 
also require immediate suspension of accrual, as deemed necessary to ensure patient 
safety.   
  
The study team then forwards the action plan to the DSMB chair for review. A copy of the 
action plan is also provided to the DOS DMSB for review at the time it is submitted to the 
FDA & IRB. The DSMB provides a prompt review of the action plan and a summary of that 
review to the IRB and to the study team. The review by the DSMB serves as an advisory 
statement to the IRB and either expresses approval of the action plan or provides 
recommendations for modifications to the plan. The suspended study may only be re-opened 
after the sponsor-investigator has received FDA approval to do so. It will not be re-opened 
without proper protocol modification.  
  
Minutes   
• 
All decisions of the DOS DSMB are maintained in the minutes of the committee. The 
decisions of the committee are also conveyed in writing to the principal investigator 
of the study, the study statistician, and the IRB. If the DOS DSMB recommends 
immediate suspension or closure of a study, the PI and or study team will receive 
written notification from the DSMB chair.   
o Principal investigators may appeal the decisions of the DOS DSMB by 
submitting a written appeal to the chair of the DSMB. If the decision 
regarding the appeal is unsatisfactory to the investigator, a second appeal may 
be made to the Chair of Surgery Research.   
• 
Suspension or closure of any FDA regulated clinical trial by the DSMB will be 
reported immediately to the FDA by the PI. If the suspension is temporary, the PI will 
notify the FDA & IRB of the steps taken to remedy the issues that led to the 
suspension.   

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9 Data Handling and Record Keeping  
9.1  Confidentiality  
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the 
following:  
• 
What protected health information (PHI) will be collected from subjects in this study  
• 
Who will have access to that information and why  
• 
Who will use or disclose that information  
• 
The rights of a research subject to revoke their authorization for use of their PHI.  
  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (long term survival status 
that the subject is alive) at the end of their scheduled study period.  
9.2  Source Documents  
  
Source data comprise all information, original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  
Source data are contained in source documents.  Examples of these original documents, and  
data records include: hospital records, clinical and office charts, laboratory notes, 
memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after verification 
as being accurate and complete, microfiches, photographic negatives, microfilm or magnetic 
media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. When applicable, information 
recorded on the CRF shall match the Source Data recorded on the Source Documents.  
  
9.3  Case Report Forms  
  
A Case Report Form (CRF) will be completed for each subject enrolled into the clinical 
study.  The investigator-sponsor will review, approve and sign/date each completed CRF; the 
investigator-sponsor’s signature serving as attestation of the investigator-sponsor’s 
responsibility for ensuring that all clinical and laboratory data entered on the CRF are 
complete, accurate and authentic.  
  
The study case report form (CRF) is the primary data collection instrument for the study.  All 
data requested on the CRF must be recorded.  All missing data must be explained.  If a space 
on the CRF is left blank because the procedure was not done or the question was not asked, 

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write “N/D”.  If the item is not applicable to the individual case, write “N/A”.  All entries 
should be printed legibly in black ink.  If any entry error has been made, to correct such an 
error, draw a single straight line through the incorrect entry and enter the correct data above 
it.  All such changes must be initialed and dated.  Do not obliterate, erase, or use “white-out” 
for errors.  For clarification of illegible or uncertain entries, print the clarification above the 
item, then initial and date it.  If the reason for the correction is not clear or needs additional 
explanation, neatly include the details to justify the correction.  
  
  
Data Security and Confidentiality  
  
Data will be entered into a secure password-protected database (REDCap) with access 
limited to the study team as delegated by the Principal Investigator.  Study participants will 
be assigned an individual code at the time of enrollment which will be applied to all of their 
data, allowing for increased confidentiality during data analysis. REDCap allows participant 
data to be downloaded in a de-identified manner and also includes and audit trail for all data 
entry and subsequent changes to data.  
  
9.4  Records Retention  
  
The sponsor-investigator will maintain records and essential documents related to the 
conduct of the study.  These will include subject case histories and regulatory documents.  
  
The sponsor-investigator will retain the specified records and reports during the study and for 
the longer of the following;  
1. As outlined in the Mayo Clinic Research Policy Manual –“Retention of and Access to 
Research Data Policy” http://mayocontent.mayo.edu/research-policy/MSS_669717,   
  
OR  
  
2. A period of 2 years after the latter of the following two dates: The date on which the 
investigation is terminated or completed, or the date that the records are no longer 
required for purposes of supporting a premarket approval application or a notice of 
completion of a product development protocol.  
10 Study Monitoring, Auditing, and Inspecting  
10.1 Study Monitoring Plan  
  
The investigator will allocate adequate time for such monitoring activities.  The Investigator 
will also ensure that the monitor or other compliance or quality assurance reviewer is given 
access to all the study-related documents and study related facilities (e.g. pharmacy, 
diagnostic laboratory, etc.), and has adequate space to conduct the monitoring visit.  

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This study will use the currently established independent Department of Surgery, Data and 
Safety Monitoring Board (DSMB) which meets quarterly.  
This study will be monitored on a routine basis during the conduct of the trial.  The Mayo 
Clinic Office of Research Regulatory Support will provide assistance and guidance with 
clinical trial monitoring activities as a service for the sponsor-investigator.  Clinical trial 
monitoring requires review of the study data generated throughout the duration of the study 
to ensure the validity and integrity of the data along with the protection of human research 
subjects.  This will assist sponsor-investigators in complying with Food and Drug 
Administration regulations.  
10.2 Auditing and Inspecting  
The sponsor-investigator will permit study-related monitoring, audits, and inspections by the 
IRB, the monitor, and government regulatory agencies, of all study related documents (e.g., 
source documents, regulatory documents, data collection instruments, study data etc.).  The 
sponsor-investigator will ensure the capability for inspections of applicable study-related 
facilities (e.g., pharmacy, diagnostic laboratory, etc.).  
  
Participation as a sponsor-investigator in this study implies acceptance of potential inspection 
by government regulatory authorities and applicable compliance offices.  
11 Ethical Considerations  
This study is to be conducted according to United States government regulations and 
Institutional research policies and procedures.  
  
This protocol and any amendments will be submitted to a properly constituted local 
Institutional Review Board (IRB), in agreement with local legal prescriptions, for formal 
approval of the study.  The decision of the IRB concerning the conduct of the study will be 
made in writing to the sponsor-investigator before commencement of this study.  
  
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study.  This consent form will be submitted with the protocol for review 
and approval by the IRB for the study.  The formal consent of a subject, using the Approved 
IRB consent form, must be obtained before that subject undergoes any study procedure.  The 
consent form must be signed and dated by the subject or the subject’s legally authorized 
representative, and the individual obtaining the informed consent.  
12 Study Finances  
12.1 Funding Source  
  
The fetal in utero repair of spina bifida is considered part of the standard of prenatal care for 
those patients including the follow-up visits mentioned before. The experimental procedure 

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proposed in the present study is going to follow the exactly same neurological technique and 
same perinatal follow-up visits, which are covered regularly by medical insurances.   
  
Therefore, the pre-surgical evaluation as well as all post-surgical visits and perinatal 
management will be considered part of the perinatal standard of care and the subject's 
insurance will be responsible for the costs associated with them.  Since the in utero repair of 
spina bifida is considered part of the standard of perinatal care, verification of insurance 
coverage will be confirmed prior to the fetal procedure.  
  
  
12.2 Conflict of Interest  
  
Any study team member who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, etc.) must 
have the conflict reviewed by a properly constituted Conflict of Interest Committee with a 
Committee-sanctioned conflict management plan that has been reviewed and approved by the 
study sponsor-investigator prior to participation in this study.  
  
  
13 Publication Plan  
  
Data obtained from this study will be publicly disclosed, whether positive or negative. 
Whenever possible, data dissemination will occur through presentation at major scientific 
conferences and/or publication in peer-reviewed journals, and will be complete, accurate, 
balanced, and timely. The study team will not misrepresent data in these scientific 
communications. We will also register this study on Clinicaltrials.gov and the enrollment of 
patients in the present study will start only after registration.  
  
  
  
  
14 References  
  
  
1. Mitchell LE, Adzick NS, Melchionne J, Pasquariello PS, Sutton LN, Whitehead AS. 
Spina bifida. Lancet 2004;364:1885-95.  
  
2. Lachmann R, Chaoui R, Moratalla J, Picciarelli G, Nicolaides KH. Posterior brain in 
fetuses with open spina bifida at 11 to 13 weeks. Prenat Diagn 2011;31:103-6.  
  
3. Case AP, Colpitts LR, Langlois PH, Scheuerle AE. Prenatal diagnosis and cesarean 
section in a large, population-based birth defects registry. J Matern Fetal Neonatal 
Med 2011.  

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4. Cameron M, Moran P. Prenatal screening and diagnosis of neural tube defects. Prenat 
Diagn 2009;29:402-11.  
  
5. Chen CP. Prenatal diagnosis, fetal surgery, recurrence risk and differential diagnosis 
of neural tube defects. Taiwan J Obstet Gynecol 2008;47:283-90.  
  
6. Adzick NS. Fetal myelomeningocele: natural history, pathophysiology, and in-utero 
intervention. Semin Fetal Neonatal Med 2010;15:9-14.  
  
7. Adzick NS, Walsh DS. Myelomeningocele: prenatal diagnosis, pathophysiology and 
management. Semin Pediatr Surg 2003;12:168-74.  
  
8. Bowman RM, McLone DG. Neurosurgical management of spina bifida: research 
issues. Dev Disabil Res Rev 2010;16:82-7.  
  
9. Fichter MA, Dornseifer U, Henke J, et al. Fetal spina bifida repair--current trends and 
prospects of intrauterine neurosurgery. Fetal Diagn Ther 2008;23:271-86.  
  
10. Holzgreve W, Feil R, Louwen F, Miny P. Prenatal diagnosis and management of fetal 
hydrocephaly and lissencephaly. Childs Nerv Syst 1993;9:408-12.  
  
11. Peiro JL, Carreras E, Guillen G, et al. Therapeutic indications of fetoscopy: a 5-year 
institutional experience. Journal of laparoendoscopic & advanced surgical techniques 
Part A 2009;19:229-36.  
  
12. Soldado F, Aguirre M, Peiro JL, et al. Fetal surgery of extremity amniotic bands: an 
experimental model of in utero limb salvage in fetal lamb. Journal of pediatric 
orthopedics 2009;29:98-102.  
  
13. Sutton LN. Fetal surgery for neural tube defects. Best Pract Res Clin Obstet Gynaecol 
2008;22:175-88.  
  
14. Fontecha CG, Peiro JL, Aguirre M, et al. Inert patch with bioadhesive for gentle fetal 
surgery of myelomeningocele in a sheep model. Eur J Obstet Gynecol Reprod Biol 
2009;146:174-9.  
  
15. Bruner JP, Tulipan N. Intrauterine repair of spina bifida. Clin Obstet Gynecol 
2005;48:942- 55.  
  
16. Bruner JP, Tulipan N, Reed G, et al. Intrauterine repair of spina bifida: preoperative 
predictors of shunt-dependent hydrocephalus. Am J Obstet Gynecol 
2004;190:130512.  
  

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17. Peiro JL, Fontecha CG, Ruano R, Esteves M, Fonseca C, Belfort, MA. Single Access 
Fetal Endoscopy (SAFE) for Myelomeningocele in Sheep Model I: Amniotic Carbon 
Dioxide Gas Approach. Surg Endosc. 2013 Oct;27(10):3835-40. doi:  
10.1007/s00464-013-2984-6. Epub 2013 May 14. PubMed PMID: 23670742  
  
18. Adzick NS, Thom EA, Spong CY, et al. A randomized trial of prenatal versus 
postnatal repair of myelomeningocele. N Engl J Med 2011;364:993-1004  
  
19. Encinas Hernandez JL, Soto C, Garcia-Cabezas MA, et al. Brain malformations in the 
sheep model of myelomeningocele are similar to those found in human disease: 
preliminary report. Pediatric surgery international 2008;24:1335-40.  
  
20. Fontecha CG, Peiro JL, Sevilla JJ, et al. Fetoscopic coverage of experimental 
myelomeningocele in sheep using a patch with surgical sealant. Eur J Obstet Gynecol 
Reprod Biol 2011;156:171-6.  
  
21. Encinas JL, Garcia-Cabezas MA, Barkovich J, et al. Maldevelopment of the cerebral 
cortex in the surgically induced model of myelomeningocele: implications for fetal 
neurosurgery. J Pediatr Surg 2011;46:713-22.  
  
22. Fontecha CG, Aguire M, Soldado F, et al. Effects of birth advancement in Chiari 
malformation in a surgical myelomeningocele model in rabbits. J Pediatr Surg 
2010;45:594-9.  
  
23. Kohl T. Minimally invasive fetoscopic interventions: an overview in 2010. Surg 
Endosc 2010;24:2056-67.  
  
24. Kohl T, Hering R, Heep A, et al. Percutaneous fetoscopic patch coverage of spina 
bifida aperta in the human--early clinical experience and potential. Fetal Diagn Ther 
2006;21:185-93.  
  
25. Peiro JL, Carreras E, Soldado F, et al. Fetoscopic release of umbilical cord amniotic 
band in a human fetus. Ultrasound Obstet Gynecol 2009;33:232-4.  
  
26. Kohl T, Tchatcheva K, Merz W, et al. Percutaneous fetoscopic patch closure of 
human spina bifida aperta: advances in fetal surgical techniques may obviate the need 
for early postnatal neurosurgical intervention. Surg Endosc 2009;23:890-5.  
  
27. Kohl T, Tchatcheva K, Weinbach J, Hering R, Koslowski P, Stressig R, Gembruch U. 
Surg Endoscop 2010;24:432-444  
  
28. Verbeek RJ, Heep A, Maurits NM, Cremer R, Hoving EW, Brouwer OF, van der 
Hoeven JH, Sival DA. Fetal endoscopic myelomeningocele closure preserves 
segmental neurological function. Dev Med Child Neurol. 2012 Jan;54(1):15-22. doi:  

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Rodrigo Ruano, MD  
  
CONFIDENTIAL  
10.1111/j.1469- 8749.2011.04148.x. Epub 2011 Nov 29.  
  
29. Belfort, MA, Whitehead WE, Shamshirsaz AA, Ruano R, Cass DL, Olutoye OO,  
Fetoscopic Repair of Meningomyelocele. Obstetrics & Gynecology: October 2015 - 
Volume 126 - Issue 4 - p 881–884; doi: 10.1097/AOG.0000000000000835, PubMed  
PMID: 25923030  
  
30. Graf K, Kohl T, Neubauer BA, Dey F, Faas D, Wanis FA, Reinges MH, Uhl E, 
Kolodziej MA. Percutaneous minimally invasive fetoscopic surgery for spina bifida 
aperta. Part III: neurosurgical intervention in the first postnatal year. Ultrasound 
Obstet Gynecol. 2016 Feb;47(2):158-61. doi: 10.1002/uog.14937. PubMed PMID: 
26138563.  
  
31. Kohl T. Percutaneous minimally invasive fetoscopic surgery for spina bifida aperta. 
Part I: surgical technique and perioperative outcome. Ultrasound Obstet Gynecol. 
2014 Nov;44(5):515-24. doi: 10.1002/uog.13430. PubMed PMID: 24891102.  
  
32. Degenhardt J, Schürg R, Winarno A, Oehmke F, Khaleeva A, Kawecki A,  
Enzensberger C, Tinneberg HR, Faas D, Ehrhardt H, Axt-Fliedner R, Kohl T. 
Percutaneous minimal-access fetoscopic surgery for spina bifida aperta. Part II:  
maternal management and outcome. Ultrasound Obstet Gynecol. 2014  
Nov;44(5):525-31. doi: 10.1002/uog.13389. PubMed PMID: 24753062.  
  
33. Belfort MA, Whitehead WE, Shamshirsaz AA, Bateni ZH, Olutoye OO, Olutoye OA, 
Mann DG, Espinoza J, Williams E, Lee TC, Keswani SG, Ayres N, Cassady CI, 
Mehollin-Ray AR, Sanz Cortes M, Carreras E, Peiro JL, Ruano R, Cass DL.  
Fetoscopic Open Neural Tube Defect Repair: Development and Refinement of a 
Two-Port, Carbon Dioxide Insufflation Technique. Obstet Gynecol. 2017 
Apr;129(4):734-743. doi: 10.1097/AOG.0000000000001941. PubMed PMID: 
28277363.