The nCYT Study: A Powered Study to Evaluate the Sensitivity and Specificity of Cytological Evaluation of Fallopian Tube Samples Collected by the Cytuity in Determining the Presence of Malignancy
Conditions: Fallopian Tube Cancer, Ovarian Cancer, Ovarian Neoplasms, Ovary Cancer, Fallopian Tube Neoplasms, Fallopian Tube Adenocarcinoma, High Grade Serous Carcinoma, Peritoneal Carcinoma, Peritoneal Neoplasms, Adnexal Mass, Ovarian Diseases
Sponsor: Boston Scientific Corporation

 
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The nCYT Study: 
A Powered Study to Evaluate the Sensitivity and 
Specificity of Cytological Evaluation of Fallopian 
Tube Samples Collected by the Cytuity™ in 
Determining the Presence of Malignancy 
 
 
Protocol Number: CLIN 0507 
Protocol synonym: nCYT 
Protocol Version: 03 
Version Date: 22OCT2019 
 
 
Boston Scientific Corporation 
300 Boston Scientific Way 
Marlborough, MA  01752 
USA 
Phone: 1-888-272-1001 
UrologyAndWomens@bsci.com 
 
 
All contents of this document are confidential as it contains sensitive Intellectual 
Property information (patents pending). No unpublished information contained 
herein may be disclosed without written permission of Boston Scientific Corporation. 
Access to this document must be restricted to relevant parties. 
 
 

 
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Synopsis of the Clinical Investigation 
Study Title 
The nCYT Study: A Powered Study to Evaluate the Sensitivity and 
Specificity of Cytological Evaluation of Fallopian Tube Samples 
Collected by the Cytuity™ in Determining the Presence of Malignancy 
Protocol Number 
CLIN 0507 
Sponsor 
Boston Scientific Corporation 
1192 Cherry Avenue 
San Bruno, CA 94066  
1-888-272-1001 
Product Name 
Cytuity™  
Regulatory Status 
The Cytuity™ has been cleared by the FDA for the following Indications 
for Use:  
“The Cytuity™ is a hysteroscope accessory, placed through the working 
channel of a hysteroscope to obtain samples from the fallopian tube for 
cytological evaluation.”  
Primary Objective 
The objective of the study is to evaluate the sensitivity and specificity 
of cytological evaluation of samples collected by the Cytuity™ in 
determining the presence or absence of malignancy in the fallopian 
tubes. 
Study Design 
The study is a prospective, multi-center, non-randomized study. Study 
subjects will be recruited from a population of women who are already 
scheduled to undergo salpingo-oophorectomy or salpingectomy. The 
study protocol requires hysteroscopic sampling of the fallopian tube 
with the Cytuity™ device at the time of scheduled surgery.  
Cytology results from the cells collected using the Cytuity™ will be 
independently evaluated at a core lab and compared to the respective 
clinical site’s histological evaluation of the excised tissue. The histology 
results will not be shared with the core lab to avoid bias. Additionally, 
cytology results will not be shared with the study’s subjects or study 
investigator as no medical decisions will be made based on Cytuity™ 
results.  
Any baseline testing, surgical histology evaluations, and all other clinical 
care will be in accordance with each participating institution’s standard 

 
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of 
care 
for 
patients 
undergoing 
salpingo-oophorectomy 
or 
salpingectomy. 
Risk Status 
The Cytuity™ device will be used in subjects at the time of scheduled 
surgery. Because the tissue that the Cytuity™ device contacts will 
subsequently be removed and because the device has been cleared by 
the FDA for use in obtaining samples from the fallopian tube for 
cytological evaluation, this study is proposed as a Non-Significant Risk 
(NSR) study. 
Investigational Sites 
Up to 15 clinical sites may participate in this study 
Number of 
Participants 
The Cytuity™ procedure will be performed on a maximum of 150 
subjects. 
Subjects will be recruited until Cytuity™ cytology results can be 
compared with the surgical histology in at least 32 subjects determined 
to have a malignant neoplasm or malignancy and 18 subjects 
determined by surgical histology of the excised tissues to be negative 
for malignancy.  
Statistical conversion from subjects to fallopian tubes yields a 
requirement of 56 tubes, or samples, positive for malignancy. This is 
because the left and right fallopian tubes are treated as partially 
independent from one another in regard to the histology results (for 
example, if there is malignancy in the right tube, that does not mean 
that there is malignancy on the left). 
Based on an assumed 20% prevalence rate of (subject-level) 
malignancy, a sample size of 140 subjects (280 tubes) in which both 
fallopian tubes are tested is statistically likely to produce the minimum 
56 positive tubes required. 
Study population 
Subjects who are scheduled to undergo a salpingo-oophorectomy or 
salpingectomy because of a pelvic mass suspicious for malignancy. 
Inclusion Criteria 
Inclusion Criteria: 
1. Subject is medically cleared for surgery  
2. Subject is scheduled to undergo salpingo-oophorectomy or 
salpingectomy for a pelvic mass suspicious for malignancy  
3. Subject must be 18 years of age 
4. Subject must be able to provide informed consent 
 

 
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Exclusion Criteria 
Exclusion criteria: 
1. Contraindication to hysteroscopy 
2. Acute pelvic inflammatory disease 
3. Active or recent lower pelvic infection 
4. Pregnancy 
5. Delivery or termination of a pregnancy in the past 6 weeks 
6. Known tubal obstruction  
7. Tubal ligation 
8. Invasive carcinoma of the cervix or endometrium 
9. Intolerance of anesthesia 
 
Study Duration 
Recruitment of subjects is expected to take approximately 12 months. 
Subjects will be on study from the time of informed consent until study 
exit, which is 24 hours post- Cytuity™ use or post-operative discharge, 
whichever occurs first. See Table 2 below for study-related contacts. 
Safety Measures  
Subjects participating in the study are already scheduled to undergo 
salpingo-oophorectomy or salpingectomy with the attendant risks and 
adverse events (pain, nausea, etc.) of that surgery. All Cytuity™ device-
related, Cytuity™ procedure-related, serious and unanticipated 
adverse events will be recorded and assessed for seriousness, severity, 
and relatedness to the study device and/or study procedure.  
Primary Endpoint 
 
The primary endpoints of the study are to evaluate the sensitivity and 
specificity of the cytological samples collected from the fallopian tube 
in determining the presence or absence of malignancy for fallopian 
tube involvement as compared to the surgical histology results.  
Fallopian tube involvement is defined as: 
1. Malignant cells that originated in the fallopian tube. This is 
detected by the surgical histology results from the fallopian 
tube. 
2. Malignant cells that have migrated to the fallopian tube. This 
can be detected by surgical histology results of the ovaries or 
fallopian tubes. 
 
 
Secondary Endpoints 
1. PPV (positive predictive value), NPV (negative predictive value), 
and Diagnostic Accuracy will be calculated for Cytuity™ as 

 
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compared to surgical histology of the ovaries and fallopian tube 
for fallopian tube involvement. 
2. Sensitivity, specificity, PPV, NPV, and accuracy will be calculated 
for Cytuity™ as compared to surgical histology of the fallopian 
tube. 
3. Sensitivity, specificity, PPV, NPV, and accuracy will be calculated 
for Cytuity™ as compared to surgical histology of the ovaries. 
4. Sensitivity, specificity, PPV, NPV, and accuracy will be calculated 
for Cytuity™ as compared to surgical histology for fallopian tube 
involvement for subject level analysis. 
Statistical Methods for 
Primary Endpoint 
The sensitivity of the Cytuity™ procedure is estimated to be 80%, while 
the specificity is estimated to be 90% for the primary endpoint of 
fallopian tube involvement.  
Since sensitivity is a function of diseased fallopian tubes only, while 
specificity is a function of non-diseased fallopian tubes, the statistical 
hypotheses for sensitivity and specificity are considered to be 
independent. Each hypothesis is framed as a 1-sided test with a type I 
error rate of 2.5%. 
For sensitivity, the following hypothesis will be tested: 
HNull: Sensitivity ≤ 60% versus  
HAlternative: Sensitivity > 60% 
For specificity, the following hypothesis will be tested:  
HNull: Specificity ≤ 70% versus  
HAlternative: Specificity > 70% 
Independent Core 
Labs 
Pathology (surgical histology/pathology): 
Site specific redacted reports reviewed by independent study 
pathologist: 
Brooke Howitt, MD 
Pathologist 
Stanford University Medical Center 
Cytology Core Lab (slide preparation) 
Calpath Medical Associates 
Campbell, CA 
Pathologist #1 (cytology review): 
Sharmila Pramanik, MD  
Pathologist  
Santa Clara Valley Medical 

 
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Pathologist #2 (cytology review) 
Eric Yang, MD 
Pathologist 
Stanford University Medical Center 
Pathologist #3 (cytology adjudication) 
Teresa Darragh, MD 
Pathologist 
University of California San Francisco 
 

 
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 Table of Contents 
 
Synopsis of the Clinical Investigation ............................................................................................ 2 
Table of Contents ......................................................................................................................... 7 
Definitions…. ............................................................................................................................... 9 
1 Introduction ............................................................................................................................ 11 
1.1 
Current Treatment ...................................................................................................... 11 
1.2 
Need for New Treatment ............................................................................................. 11 
1.3 
Investigational Product................................................................................................ 11 
1.4 
Manufacturer .............................................................................................................. 12 
1.5 
Regulatory Classification ............................................................................................. 12 
1.6 
Device Accountability .................................................................................................. 13 
1.7 
Intended Purpose of the Device in the Clinical Investigation ......................................... 13 
1.8 
Required Training and Experience Needed to Use the Device ....................................... 13 
1.9 
Study Overview ........................................................................................................... 14 
2 Justification for Clinical Investigation Design ............................................................................ 17 
3 Risks and Benefits of the Investigational Device and Clinical Investigation ................................ 17 
3.1 
Anticipated Clinical Benefits ........................................................................................ 17 
3.2 
Anticipated Adverse Events and Adverse Device Effects ............................................... 17 
3.3 
Risk Mitigation ............................................................................................................ 19 
3.4 
Risk-to-Benefit Rationale ............................................................................................. 19 
4 Objective…. ............................................................................................................................. 19 
5 Design of the Clinical Investigation .......................................................................................... 20 
5.1 
General ....................................................................................................................... 20 
5.2 
Participants ................................................................................................................. 20 
5.3 
Procedures .................................................................................................................. 22 
5.4 
Monitoring Plan .......................................................................................................... 26 
6 Statistical Considerations ........................................................................................................ 27 
6.1 
Hypothesis .................................................................................................................. 27 
6.2 
Primary Outcome ........................................................................................................ 28 
6.3 
Secondary Outcomes ................................................................................................... 29 
6.4 
Sample Size Determination .......................................................................................... 29 
6.5 
Statistical Methods ..................................................................................................... 30 
7 Data Management .................................................................................................................. 31 
7.1 
Case Report Forms ...................................................................................................... 31 
7.2 
Data Management ...................................................................................................... 31 
7.3 
Data Retention ............................................................................................................ 31 
8 Protocol Amendments ............................................................................................................. 32 
9 Protocol Deviations ................................................................................................................. 32 
9.1 
Corrective and Preventive Actions ............................................................................... 32 
9.2 
Investigator Disqualification Criteria ............................................................................ 32 
10 Statements of Compliance ..................................................................................................... 33 
10.1 
Investigator Responsibilities ........................................................................................ 33 
10.2 
Institutional Review Board (IRB) Requirements ............................................................ 33 
11 Informed Consent Process ..................................................................................................... 34 

 
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12 Adverse Events ...................................................................................................................... 34 
12.1 
Severity ...................................................................................................................... 34 
12.2 
Relatedness ................................................................................................................ 34 
12.3 
Reporting Requirements .............................................................................................. 35 
12.4 
Procedures for Reporting SAEs and UADEs ................................................................... 35 
13 Suspension or Premature Termination of the Study ................................................................ 35 
14 Revision History .................................................................................................................... 35 
 
 
 

 
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Definitions 
Adverse Event (AE): any untoward medical occurrence, unintended disease or injury, 
or untoward clinical signs (including abnormal laboratory findings) in participants, 
users or other persons, related to the investigational medical device or study 
procedure. 
 
Adverse Device Effect (ADE): adverse event related to the use of an investigational 
medical device. 
Serious Adverse Event (SAE): an adverse event, per the FDA, is serious when the 
patient outcome is  
death 
life-threatening  
disability or permanent damage 
hospitalization* – initial or prolonged (>24 hours) 
required (medical or surgical) intervention to prevent permanent impairment or 
damage  
congenital anomaly / birth defect 
other serious (important medical events) 
 
*Note: Planned hospitalization for a pre-existing condition is not considered a 
serious adverse event. 
 
Serious Adverse Device Effect (SADE): adverse device effect that has resulted in any 
of the consequences characteristic of a serious adverse event. 
 
Unanticipated adverse device effect (UADE): means 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)] 
 
Seriousness:  
Mild Severity: means the subject is aware of signs or symptoms, but easily 
tolerates them. 
 
Moderate Severity: means the subject has discomfort enough to cause 
interference with usual activity 
 
Severe Severity: means the subject is incapacitated by an inability to work or 
do usual activity 
 
 
 

 
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Relatedness: relatedness to both the Cytuity™ device and Cytuity™ study procedure 
(including AEs related to the use of the hysteroscope) will be reported. 
 
Not related:  means there is an adverse event for which sufficient information 
exists to indicate that there is no causal connection between the event and the 
investigational device or study procedure. The adverse event is due to and 
readily explained by the participant’s underlying disease state or is due to 
concomitant medication or therapy not related to the use of the device or the 
procedure. In addition, the adverse event may not follow a reasonable 
temporal sequence following the treatment procedure. 
 
Possibly related:  means there is a reasonable possibility that the adverse 
event may have been primarily caused by the investigational device and/or 
study procedure. The adverse event has a reasonable temporal relationship to 
the use of the device or the study procedure and follows a known or expected 
response pattern to the investigational device or study procedure, but 
alternative etiology is equally or more likely compared to the potential 
relationship to the use of device or the study procedure. 
 
Definitely related:  is an adverse event that can only be attributed to the 
investigational device and/or study procedure. 
 
Positive Predictive Value (PPV): the probability that subjects with positive screening 
test (positive cytology results) truly have the disease (when compared to surgical 
histology results) 
 
Negative Predictive Value (NPV): the probability that subjects with a negative 
screening test (negative cytology results) truly do not have the disease (when 
compared to surgical histology results) 
 
Accuracy (diagnostic accuracy): the degree to which the diagnostic result (cytology 
result) conforms to the correct diagnosis (based on surgical histology results). 
 
Sensitivity: the ability of a diagnostic test (cytological evaluation of samples collected 
from the Cytuity™ device) to correctly identify those with the disease (true positive 
rate).  
 
Specificity: the ability of the diagnostic test (cytological evaluation of samples 
collected from the Cytuity™ device) to correctly identify those without the disease 
(true negative rate). 
 
Adequate Sample:  a sample where background and artifact do not impact review of 
cellular detail and the sample contains more than five clusters or has less than five 
clusters but contains neoplastic or malignant cells.  
 
 
 

 
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1 Introduction 
 
Current Treatment  
Histological evaluation of surgically excised fallopian tube and ovarian tissue is 
considered the gold standard for determining the presence of malignancy. No 
accurate and/or reliable diagnostic test exists for ovarian or fallopian tube 
malignancy. For example, the most commonly used blood test for ovarian cancer 
today has a sensitivity of as low as 32% for diagnosing early stage ovarian 
cancer.1,2,3,4,5,6,7,8,9,10 It should be noted that this gold standard, histology of excised 
tissue, requires invasive surgery and removal of the anatomy, and therefore is 
considered an aggressive and drastic, sometimes necessary option for accurate 
diagnosis.  
 
Need for New Treatment 
The benefits of developing a system/device that could atraumatically, and minimally 
invasively, collect cells from the fallopian tube that could be evaluated cytologically 
for the presence or absence of atypical or malignant features are expected to be 
significant as current tests lack both sensitivity and specificity. Cytologic evaluation 
of cells collected from the female genital tract has yielded clinically useful 
information since the 1920s11. Evaluation of cells for atypical or malignant features 
has been used effectively to identify individuals who may be at increased risk for 
malignancy.  
Work was done to develop a minimally invasive method for cell collection from the 
fallopian tube, but until the MAKO 7 device (now called Cytuity™ device) was 
developed, no such method has reliably collected cells from this part of the anatomy. 
In one ten (10) patient study, a standard brush biopsy catheter could not be passed 
through the length of the fallopian tube in patients, neither hysteroscopically nor 
laparoscopically.12 Access to the fallopian tube has been challenging due to its 
significant tortuosity and narrow inner diameter, as well as lack of tactile feedback 
provided by the consistency of the wall of the fallopian tubes. 
 
Investigational Product 
nVision Medical developed the MAKO 7 device to be used through the working 
channel of a hysteroscope for cell collection from the fallopian tube. nVision Medical 
was acquired by Boston Scientific Corporation in 2018 and the MAKO 7 is now called 
Cytuity™.  The MAKO 7 and Cytuity devices are equivalent. The MAKO 7 / Cytuity™ 
device is FDA cleared as a hysteroscope accessory, placed through the working 
channel of a hysteroscope to obtain samples from the fallopian tube for cytological 
evaluation.  

 
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In a previous study, undertaken and submitted in support of FDA clearance, the 
MAKO 7/ Cytuity™ device was evaluated in forty (40) subjects (80 fallopian tubes) 
who were already scheduled to undergo a laparoscopic tubal ligation. Study 
endpoints included 1) ability of the device to navigate the fallopian tube, 2) ability of 
the device to collect a sample adequate for cytological evaluation, and 3) adverse 
events. Access was achieved in 71/71 (100%) of unblocked fallopian tubes and 71/80 
(89%) of all tubes attempted. The nine (9) tubes that were not accessed were 
determined to have pre-existing tubal occlusion, as determined by methylene blue 
dye injection. The study pathologist determined that 70/71 (99%) of the samples 
were adequate for cytological evaluation. There were no adverse events reported. 
A subsequent study was undertaken with the purpose of demonstrating the 
effectiveness of the MAKO 7 / Cytuity™ device in collecting samples from the 
fallopian tube for cytological evaluation that were adequate to enable determination 
and/or differentiation of normal versus atypical versus malignant cells. Furthermore, 
for information only, sensitivity and specificity for malignancy were assessed. The 
study was a prospective, multi-center, observational study of 50 subjects. The study 
subjects were already scheduled to undergo salpingo-oophorectomy for a pelvic 
mass suspicious for malignancy or for BRCA1 or BRCA2 mutations. The protocol 
required hysteroscopic sampling of cells from the fallopian tube with the MAKO 7 / 
Cytuity™ device. Fallopian tube cytology results were then compared to fallopian 
tube histology results generated from the evaluation of surgically excised fallopian 
tube specimens and examined by the study site pathology department. For further 
evaluation, fallopian tube cytology results were compared to histology results of the 
ovaries as well. The MAKO 7 / Cytuity™ device was able to obtain samples that were 
adequate to enable the determination and/or differentiation of normal versus 
atypical versus malignant cells with an overall percent agreement (concordance) 
between fallopian tube cytology and fallopian tube cytology of 95%. The MAKO 7 / 
Cytuity™ device also signaled a sensitivity and specificity of 100% for fallopian tube 
involvement. 
This current study seeks to provide additional information on sensitivity and 
specificity in a larger patient population. 
 
Legal Manufacturer 
Boston Scientific Corporation 
300 Boston Scientific Way 
Marlborough, MA  01752, United States 
 
Regulatory Classification 
The Cytuity™ device is a class II device cleared by the FDA [K160510] with the 
following indication for use: 

 
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“The Cytuity™ is a hysteroscope accessory, placed through the working channel of a 
hysteroscope to obtain samples from the fallopian tube for cytological evaluation.”  
In this study, the Cytuity™ device will be used in subjects at the time of scheduled 
salpingo-oophorectomy or salpingectomy. Because the tissue that the Cytuity™ 
device contacts will be removed and because the device has been cleared by the FDA 
for use in obtaining samples from the fallopian tube for cytological evaluation, this 
study is proposed as a Non-Significant Risk (NSR) study.  
 
Device Accountability 
The sponsor and investigator are jointly responsible for the accountability of every 
unit of investigational product used for the clinical study.  
An inventory of sterile investigational Cytuity™ devices will either be shipped or hand 
carried to the investigational site by the sponsor.  
It is the responsibility of the clinical Investigator to ensure that all investigational 
products received at the site are inventoried and accounted for throughout the 
study. A device accountability log will be used to record device receipts, use, and 
disposition at the site. This log will be maintained in the site study file.  
 
Intended Purpose of the Device in the Clinical Investigation 
The objective of this study is to evaluate the sensitivity and specificity, estimated to 
be 80% and 90% respectively, of cytological evaluation of samples collected by the 
Cytuity™ device in determining the presence or absence of malignant cells that 
originated in the fallopian tube or malignant cells that have migrated to the fallopian 
tubes. The Cytuity™ device is currently cleared for cell collection from the fallopian 
tube. This study is not intended to provide data regarding the rate of successful cell 
collection. 
 
Required Training and Experience Needed to Use the Device 
As cleared by the FDA, the Cytuity™ device requires that the device is “…to be used 
only by physicians who are knowledgeable hysteroscopists.” 
Since this study requires access to an enriched patient population, i.e. patients who 
have malignancies, investigators may include gynecologic oncologists rather than the 
target user, gynecologists who are skilled at hysteroscopy. As a result, training not 
typically required of the target user will be provided for all investigators. Lower 
Cytuity™ device access rates and lower sample adequacy rates may be expected with 
this investigator population.  
Prior to the start of the study, the investigator and clinical study staff will undergo 
training on the use of Cytuity™ device, the clinical study protocol, and study 

 
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procedures and requirements. Sponsor personnel (or designees) will conduct the 
training.  
Clinical research staff will be supplied with the clinical protocol, device instructions 
for use, case report forms, and other supporting materials as needed.  
Training of study personnel will be documented on the appropriate training record 
and maintained in the site study file and in the sponsor’s trial master file.  
 
Study Overview 
The study is a prospective, multi-center, non-randomized study. Subjects will be 
recruited from a population of women who are already scheduled to undergo 
salpingo-oophorectomy or salpingectomy.  
The procedure requires hysteroscopic sampling of the fallopian tube with the Cytuity™ 
device at the time of scheduled surgery. A skilled hysteroscopist or a gynecologist who 
has undergone the sponsor’s training module is required to perform the procedure.  
Directly before the scheduled surgery, fallopian tube cytology collection will be 
performed with the Cytuity™ device. Following placement of the hysteroscope, the 
fallopian tube ostium is located, the distal tip of the Cytuity™ device will be placed at 
the tubal ostium and the balloon will be deployed into the fallopian tube. Cells are 
captured on the surface of the balloon. The balloon will then be retracted into the 
device’s sheath. The device is then withdrawn from the working channel of the 
hysteroscope and the distal end of the device containing the sheathed-balloon will be 
cut and immersed into a specimen container with a sufficient volume of 
cytopreservative. This process is repeated for the contralateral fallopian tube and the 
device is placed into a separate labeled specimen tube. The hysteroscope is removed 
before any laparoscopic insertion or surgery is performed. 
The specimen containers holding the cut end of the device will be transferred to the 
central study core lab for slide preparation, which will be used for all sites. Cytology 
samples will be prepared and analyzed using the Pap stain method. The slide(s) are 
sent to study pathologist#1 for cytology case report form completion which will 
include classification of the cytology sample into the following categories: positive 
(malignant or neoplastic) or negative (benign or atypical). The case report form is 
reviewed by the sponsor. 
The slides will then be sent to study pathologist #2 for review and classification of the 
cytology sample into the following categories: positive (malignant or neoplastic) or 
negative (benign or atypical). Upon completion the case report forms are reviewed by 
the sponsor and study slides are sent back to the sponsor.  

 
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The sponsor compares the cytology results between pathologist #1 and pathologist #2 
for 
concordance. 
Concordant 
results 
are 
later 
compared 
to 
surgical 
pathology/histology. If there is discordance, the slides are held for adjudication with 
pathologist #3. Pathologist #3 meets with both other pathologists to review the slides 
and evaluates the sample.  Pathologist #3 completes the case report form and makes 
the final determination through concordance with either pathologist #1 or pathologist 
#2.  
Once the ovary(ies) and/or fallopian tube(s) have been surgically excised, they will be 
sent to the pathology department/center of the clinical site. They will then be analyzed 
according to standard of care (including micro-sectioning of the fallopian tube); no 
unique or experimental methods for evaluation should be used. The site’s surgical 
pathology report is redacted and sent to an independent study pathologist to 
complete the histology/pathology case report form (CRF). When malignancy is 
present, the form will be marked positive.  When benign, benign mass or cyst, or 
inflammatory changes are present, the form will be marked negative. The completed 
form is returned to the sponsor. The surgical pathology source documents remain at 
the clinical site.  
Fallopian tube cytology results from two independent and concordant and/or 
adjudicated results will then be compared to surgical pathology/histology results 
independently generated from the surgically excised fallopian tube and ovarian tissue 
specimens.  
Figure 1 below illustrates the study flowchart. 
Note that any baseline testing, pathology (histology) evaluations, and all other clinical 
care will be in accordance with each participating institution’s standard of care for 
patients undergoing salpingo-oophorectomy or salpingectomy.  
 
 

 
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Patient presents with conditions (mass) 
necessitating salpingo-oophorectomy or 
salpingectomy.
Patient consented.
Directly before the surgery, 
the Cytuity procedure is 
performed. The Cytuity device 
is inserted and cells (for 
cytology) are collected.
Cytuity and hysteroscope 
removed.
Cytuity distal tip is immediately cut-off & immersed into a labeled (pt unique 
study ID # and L or R) specimen container with cytopreservative. The cell sample 
sent to the study core lab.
Salpingo-oophorectomy or 
salpingectomy surgery 
performed.
Cytology workup performed using standard Pap stain methods. Slide(s) are 
created and sent to pathologist #1.
Results of 1st cytology evaluation documented on cytology CRF. CRF reviewed by 
sponsor and slide(s) sent to pathologist #2
Slide(s) to 2nd independent 
pathologist for 2nd 
independent cytology 
evaluation.
Results of 2nd cytology 
evaluation documented on 
separate 2nd cytology CRF. CRF 
reviewed by sponsor and 
slide(s) sent back to sponsor.
Resected tissue(s) sent to the 
sites’ pathology lab for 
processing. Pathology report is 
produced by surgical 
pathologist for gyn-oncologist.
Sponsor compares 1st vs. 2nd 
cytology results for 
concordance.
Agree
Disagree
Sponsor arranges for slide(s) to 
be adjudicated
Results of 3rd cytology 
evaluation documented on  
adjudicating cytology CRF and 
slide(s) held by sponsor.
Sponsor comparison made between surgical 
pathology/histology CRF report and the 
cytology CRF report(s) for concordance.
Redacted surgical pathology/
histology provided for study 
pathologist review
Redacted surgical pathology/
histology report provided to 
independent study pathologist  
for review and completion of 
the independent surgical 
histology/pathology CRF.
 
Figure 1. Study Flowchart 
 
 

 
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2 Justification for Clinical Investigation Design 
Direct biopsy using the Cytuity™ device can collect cells from the fallopian tube for 
cytological evaluation in women, including those presenting with a pelvic mass suspicious 
for malignancy. A high sensitivity would allow gynecologists to better diagnose disease in 
its early stages, while a high specificity would send patients to surgery only if they have 
signs of disease. 
Subjects participating in this study are already scheduled to undergo salpingo-
oophorectomy or salpingectomy with the attendant risks of that surgery. The study 
device and procedure present minimal additional risk to subjects participating in this 
study, since the contacted anatomy will be removed from the subject immediately after 
study device use and because the device has received FDA clearance for collecting cells 
from the fallopian tube.  
There is no risk for inaccurate diagnosis using the Cytuity™ device as cytology results will 
not be shared with the study’s subjects or the investigator to prevent any medical 
decisions being based on Cytuity™ results. The subject’s treatment following the Cytuity™ 
procedure will be the same standard of care that the subject would have received 
without participating in this study.  
3 Risks and Benefits of the Investigational Device and Clinical 
Investigation 
The sponsor undertook a risk management process to analyze the hazards associated 
with the device in accordance with the requirements of a quality management system 
and ISO 14971.13 This process determined those events or attributes of the device that 
could pose a hazard to the patient or user, and the steps necessary to mitigate those 
hazards to an acceptable level. Risk reduction and control measures were implemented 
to reduce the residual risk as far as possible, and no remaining risk factors were found 
requiring additional action at this time. The anticipated clinical benefits and anticipated 
adverse events or device effects are detailed below. 
 
Anticipated Clinical Benefits 
While there are no direct benefits to the subject’s participating in the study, 
participation will provide information about the study device that could benefit 
other women in the future. 
 
Anticipated Adverse Events and Adverse Device Effects 
Per the device instructions for use, there are risks associated with hysteroscopy and 
use of the Cytuity™ device.  

 
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Additionally, in this study, there are risks associated with general anesthesia as the 
patient is scheduled to undergo general anesthesia for their scheduled salpingo-
oophorectomy and/or salpingectomy. 
Risks related to anesthesia or hysteroscopy include: 
• Nausea / vomiting 
• Dizziness / light headedness 
Risks related to hysteroscopy include: 
• 
Cramping 
• 
Bleeding/spotting 
• 
Vaso-vaginal response 
• 
Hypervolemia 
• 
Infection 
• 
Perforation of the uterus or fallopian tubes, with possible injury to bowel, 
bladder, or surrounding blood vessels. 
Table 1. Potential Adverse Events related to the Cytuity™ device and Mitigation Strategy 
Risk 
Mitigation 
Perforation of the 
fallopian tube is a risk 
because of its tortuosity 
and narrow dimensions. 
 
a. No rigid portion of the device enters the fallopian tube. 
Instead, a very small balloon (less than 1 mm diameter) 
is everted through the tube. Because the balloon is self-
navigating, the eversion of the balloon will minimize the 
physician’s manual advancement of the device through 
the tube and therefore the risk of perforation is 
expected to be minimized.  
b. A salpingo-oophorectomy or salpingectomy will be 
performed directly after the Cytuity™ device procedure. 
A foreign object will be 
introduced into the 
subject and therefore 
infection may occur. 
c. A sterilized device will be supplied to the physician. 
d. The device instructions for use mandate sterile 
technique. 
This study could prolong 
the time the subject is 
under general anesthesia 
by an estimated 5-7 
minutes per Cytuity™ 
device use. 
e. Prior to the study, the physician will be trained on the 
bench on how to use the Cytuity™ device accurately 
and in an efficient manner, therefore minimizing overall 
time of the procedure.  

 
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Risk Mitigation 
Subjects participating in the study are already scheduled to undergo salpingo-
oophorectomy or salpingectomy with the attendant risks of that surgery. Any events 
that occur as a result of the planned surgery will be medically managed by the 
subject’s physician per the institution’s standard of care. The study device and 
procedure present minimal additional risk to subjects participating in this study, 
since the contacted anatomy will usually be removed from the subject immediately 
after study device use and because the device is FDA cleared for cell collection from 
the fallopian tube. Standard risks associated with hysteroscopic instruments include 
perforation, infection and bleeding. It is not expected that the Cytuity™ device is 
associated with any increased risks as compared to commercially available 
hysteroscopic instruments. The Cytuity™ device procedure will increase the amount 
of time that the subject is under general anesthesia by an estimated 5-7 minutes per 
Cytuity™ device use. Additional Cytuity™ risks and mitigations are noted in Table 1 
above. There is the potential that unknown risks exist.  
This investigation will be conducted by investigators that are qualified by training 
and experience in the treatment of patients presenting for salpingo-oophorectomy 
or salpingectomy. Adequate measures including eligibility criteria limitations, subject 
screening and pre-visit assessment of their health condition have been incorporated 
into the clinical investigation to minimize such risks.  
Investigators are also familiar in the use of hysteroscopes or have gone through the 
sponsor’s training module.  
 
Risk-to-Benefit Rationale 
The sponsor believes that any potential risks presented by this investigation have 
been minimized and that the overall residual risk is deemed acceptable. 
The study device and procedure present minimal additional risk to subjects 
participating in this study, since the contacted anatomy will be removed from the 
subject immediately after study device use. 
4 Objective 
The primary objective of the study is to evaluate the sensitivity and specificity, estimated 
to be 80% and 90% respectively, of cytological evaluation of samples collected by the 
Cytuity™ device in determining the presence or absence of malignant cells that originated 
in the fallopian tube or malignant cells that have migrated to the fallopian tubes. The 
results obtained from the cytological samples will be compared against the results 

 
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obtained from the gold standard. The gold standard is the surgical histology (pathology) 
assessment of the fallopian tubes, and in cases of malignant cell migration, the ovaries.  
5 Design of the Clinical Investigation 
 
General 
This clinical investigation is a prospective, multi-center, non-randomized study. 
Subjects will be recruited from a population of women who are already scheduled to 
undergo salpingo-oophorectomy or salpingectomy. The study protocol requires 
hysteroscopic sampling of the fallopian tube with the Cytuity™ device immediately 
prior to the scheduled surgery.  
Cytology results from the cells collected using the Cytuity™ device will be 
independently evaluated at two pathologists. Concordant and/or adjudicated 
cytology results are compared to the site’s surgical histology results from the 
removed tissue(s).  
Pathology results (histology) will not be shared with pathologists conducting 
cytology evaluations and cytology results will not be shared with the site or the 
pathologist evaluating histology evaluations to remove bias. Additionally, cytology 
results will not be shared with the study’s subjects or investigator as no medical 
decisions will be made based on Cytuity™ results.  
Any baseline testing, pathology (histology) evaluations, and all other clinical care will 
be in accordance with each participating institution’s standard of care for patients 
undergoing salpingo-oophorectomy or salpingectomy. 
 
Participants 
The study population will include participants presenting with a pelvic mass 
suspicious for malignancy who are already scheduled to undergo a salpingo-
oophorectomy or salpingectomy. Screening of these participants is done to 
determine if they meet inclusion and exclusion criteria. 
 Inclusion Criteria 
A participant may be enrolled in this study if she meets all of the following criteria: 
1. Subject is medically cleared for surgery 
2. Subject is scheduled to undergo salpingo-oophorectomy or salpingectomy 
for a pelvic mass suspicious for malignancy 
3. Subject must be 18 years of age 
4. Subject must be able to provide informed consent 
 

 
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 Exclusion Criteria 
1. Contraindication to hysteroscopy 
3. Acute pelvic inflammatory disease 
4. Active or recent lower pelvic infection 
5. Pregnancy 
6. Delivery or termination of a pregnancy in the past 6 weeks 
7. Known tubal obstruction 
8. Tubal ligation 
9. Invasive carcinoma of the cervix or endometrium 
10. Intolerance of anesthesia 
 Screen Failures and Enrollment 
Any individual participant that fails to meet inclusion and exclusion criteria is 
considered a screen failure. 
Screen failures can occur prior to enrollment or after enrollment. Screen failures 
that occur prior to enrollment are logged but no other study data is collected or 
analyzed. A participant is considered enrolled in the clinical investigation after she 
has provided written informed consent.  
When an enrolled subject fails to meet inclusion and exclusion criteria, no 
additional data beyond baseline and reason for screen failure need be collected.  
 Analysis Data Sets 
An enrolled subject may voluntarily withdraw consent at any time during the 
study. Additionally, enrolled subjects may be withdrawn by the investigator (e.g. 
if the investigator determines hysteroscopy will not be attempted). The reason 
for withdrawal will be documented.  
Once the subject is enrolled, the hysteroscope is placed and ostia identified, the 
subject is part of the intent to treat (ITT) population. Subjects may still be screen 
failures after hysteroscopic visualization of the ostia if they fail any other eligibility 
criteria such as discovery of tubal ligation. Screen failures are not part of the ITT 
data set but are part of the enrolled data set.  
The modified intent to treat (mITT) population are those subjects with an 
adequate Cytuity™ cell sample. Primary and secondary endpoints will be 
evaluated using this mITT population. 
 Enrollment Duration 
The enrollment period is expected to take approximately 12 months.  

 
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 Total Expected Clinical Investigation Duration 
Recruitment of this study is expected to take approximately 12 months followed 
by data analysis. Individual study participation is approximately 1 day after the 
study procedure. 
 
Procedures 
 Consenting Visit or Contact  
Patient charts (medical history, including pregnancy test for females of child 
bearing potential) will be previewed for study eligibility, but no study-specific 
information will be collected on study case report forms before informed consent.  
It is typical to ensure that prior to performing the salpingo-oophorectomy or 
salpingectomy, the subject is tested for pregnancy (for females of childbearing 
potential). This test is therefore part of the standard of care.  
If the subject meets all pre-procedure eligibility criteria and agrees to participate 
in the study, written informed consent will be obtained. 
Medical history and demographics related to the study procedure are collected 
on case report forms following informed consent.  
 Study Treatment  
Cytuity™ procedures for collection of cells from the fallopian tube will be 
performed immediately prior to the scheduled salpingo-oophorectomy (S-O) or 
salpingectomy.  
As shown in Figure 2, the device is comprised of a catheter and a handle. The 
catheter includes a balloon, a shaft (which is made up of a stainless steel tube and 
a Nylon tube), a sheath, and a sheath knob. The handle includes a drive wheel and 
a Luer in the handle body. The Luer attaches to a commercially available inflation 
device via a stopcock supplied with Cytuity™.  
Figure 2. Cytuity™ device 
 
 

 
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Outside the body, the Cytuity™ device is prepared by pressurizing the balloon and 
pre-extending the sheath and balloon 1.5cm.  
The Cytuity™ device is pressurized using a commercially available inflation device 
that is attached to the device Luer. The sheath knob is then advanced 
approximately 1.5cm forward to the preparation mark. By rotating the drive 
wheel, the balloon is then extended forward until the tip of the balloon aligns 
with the tip of the extended sheath. The preparation is complete and the inflation 
device is then removed.  
Just prior to the scheduled S-O or salpingectomy surgery, the physician inserts the 
hysteroscope into the subject and visualizes the tubal ostia. Upon successful 
visualization, the prepared Cytuity™ device is inserted into the working channel 
of the hysteroscope until the distal tip of the catheter is positioned immediately 
proximal to the ostium of a fallopian tube. The handle is advanced to cannulate 
the ostium with the pre-extended balloon. Then the balloon is further advanced 
into the fallopian tube by rotating the drive wheel.  
Cells are collected from the fallopian tube on the surface of the balloon. Then the 
balloon is deflated by relieving pressure using the stopcock. The device is then 
retracted into the sheath and removed from the working channel of the 
hysteroscope and from the subject. Alternatively, the hysteroscope may remain 
in the subject for cell collection at the contralateral tubal ostium. A second 
Cytuity™ device is used for the second collection. Upon each Cytuity™ device 
removal from the subject, both balloon and sheath (distal tip) are to be 
simultaneously cut off and immersed into cytopreservative by stirring to agitate 
the cells. The vial is labeled with the unique subject’s study ID#, and “L” for left or 
“R” for right tube. 
Complete instructions are provided in the Cytuity™ device instruction for use 
(DFU) provided with each study device.  
Following Cytuity™ use, the hysteroscope is removed. The surgical 
instrumentation can then be placed and the subject proceeds to the planned 
surgery.  
A cytology specimen log will be completed to show transfer of the vials from the 
site either directly to the cytology core lab or to the sponsor as an interim provider 
of transport to the cytology core lab.  
Samples may be stored at room temperature pending transfer if needed.  

 
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 Prior to Study Exit 
Subjects are exited 24 hours post- Cytuity™ use or at discharge, whichever occurs 
first. The only time the follow-up period is extended is if the subject has a Cytuity™ 
study or device-related adverse event. In these instances, the subject is followed 
until the investigator deems the adverse event is resolved or for 30 days, 
whichever comes first. 
 
The following data is collected at the day of study exit: 
• Any adverse events up to study exit 
• The reason for study exit (e.g. completion of the study) 
The subject has no additional visits or follow-up required. See Table 2. 
Table 2. Schedule of Assessments 
 
Screening / 
Informed 
Consent  
Cytuity™ Study 
Procedure/ Salpingo-
oophorectomy or 
salpingectomy  
Subject 
Study 
Exit  
Lab Test 
Results (no 
subject 
involvement) 
Window (days) 
-21 
0 
+1* 
NA 
Medical 
History, 
including 
review 
of 
pregnancy status (for women of child 
bearing age)  
X 
 
 
 
Demographics 
X 
 
 
 
Inclusion / exclusion criteria determination 
X 
 
 
 
Informed Consent 
X 
 
 
 
Pregnancy Test** 
X 
 
 
 
Cell Collection using Cytuity™ device 
 
X 
 
 
Adverse Events 
 
X 
X 
 
Cytology and Surgical Histology Results 
 
 
 
X 
*Unless a Cytuity™ study or device related AE occurs, in which case the AE will be followed until resolution or 
for 30 days, whichever comes first. 
**Pregnancy test must be within 21days of study procedure. 
 
 Post-Operative Pathology  
Per site standard procedures, excised tissue will be sent to site-specific pathology 
department/facility. The histological evaluation will include standard of care only 
(including micro-sectioning of the fallopian tubes); no different, unique or 
experimental methods will be used. 

 
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Transfer of each subject’s surgical pathology (histology) report diagnostic data is 
a study requirement. All protected health information will be redacted by the site 
and the report will be labeled with the subject’s study identification number. The 
redacted histology report will be provided to the sponsor. The redacted report 
will be reviewed by an independent study pathologist who will complete the study 
histology case report form. The study pathologist reviewing histology may contact 
the site’s surgical pathology lab for clarification of the redacted report if 
warranted. If clarification is required, all communications between the site 
pathology lab and the study pathologist reviewing histology must be attached to 
the redacted report and included in the study data. 
The study pathologist will use the redacted site pathology report to document the 
histology results of fallopian tube malignancy, ovarian malignancy, and other 
malignancy on a study case report form.  
 Post-operative Cytology 
Cytuity™ collected cytology samples will be delivered to the sponsor and then the 
core lab for slide preparation.   
The core lab will be responsible for logging in received samples and processing 
the samples into slides. This requires a centrifugation step and the creation of a 
monolayer preparation on a microscope slide with the recovered fallopian tube 
cells. The slide will be stained to make the cells visible using the Pap stain method. 
The slide(s) are then transferred to Pathologist #1.  Pathologist#1 will review and 
interpret the slides for evidence of malignancy. 
Pathologist #1 will document the cytology results of the fallopian tube samples 
on a study case report form for sponsor review.  The sponsor will then forward 
the slide(s) labeled with the patient study ID number to pathologist #2. The 2nd 
pathologist will review and interpret the slides for evidence of malignancy. 
Pathologist #2 will document the cytology results of the fallopian tube samples 
on a study case report form for sponsor review.  The slide(s) are returned to the 
sponsor.  
The sponsor will review the results between pathologist #1 and pathologist #2 for 
concordance. If the results are in agreement (concordant), the sponsor will 
compare the concordant cytology results with the surgical histology/pathology 
results. If the cytology results are not in agreement (discordant), the sponsor will 
arrange for pathologist #3 to adjudicate.  The adjudicating pathologist will review 
and interpret the slide(s) for evidence of malignancy. He/she will likely agree with 
either pathologist #1 or #2, ultimately providing the final cytology result. The 
results will be recorded on a CRF. The adjudicating pathologist’s interpretation is 

 
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final. The slide(s) and CRF are returned to the sponsor for final comparison to the 
independent pathology (histology) case report forms.  
 Activities Performed by Sponsor or Sponsor Representatives  
The sponsor or designee will conduct all site investigator training, site staff 
training, core lab training, study pathologist training and site initiation visits. 
One or more representatives of the sponsor may be present during the study 
procedure at the request of the investigator and under supervision of the 
investigator to assist with device preparation prior to subject use; to assist with 
collecting holding the cell collection vial after subject use; and secure sample 
transfer to the cytology core lab post subject use.  
The sponsor may transfer cytology samples from the sites to the core cytology lab 
and then to and from pathologists reviewing cytology slides. The site’s histology 
lab and study pathologist reviewing histology are blinded to the results of the 
cytology core lab and the pathologists reviewing cytological slides. 
The sponsor or designee will monitor sites as detailed below in the section titled 
Monitoring Plan.  
The sponsor will complete all data review, statistical analysis, and write the final 
study report.  
Boston Scientific personnel will not do the following: 
• Practice medicine. 
• Provide medical diagnosis or treatment to subjects. 
• Discuss a subject’s condition or treatment with a subject. 
• Independently collect critical study data (defined as primary or secondary 
endpoint data). 
• Enter data in electronic data capture systems or on paper case report 
forms. 
 
Monitoring Plan 
Study site monitoring will be performed by qualified monitors who may be 
employees or consultants to the sponsor or a qualified CRO selected by the sponsor. 
Each site will be visited regularly in an effort to ensure that the study is conducted in 
compliance with the study protocol and all applicable guidelines, laws and 
regulations.  

 
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To monitor, study visits may include, but are not limited to, the review of device 
supply, presence of required documents, the informed consent process, and 
comparison of CRFs with source documents found in the subject’s medical records. 
Monitoring will also include the assessment of the site’s overall progress, including 
but not limited to the site’s ability to keep accurate records and to report study 
related data to the study sponsor in a timely fashion.  
The investigator agrees to participate in study visits conducted at a reasonable time, 
in a reasonable manner. 
In addition to study related logs, plans, and IRB approved documents (protocol, 
informed consent, etc.), investigators must maintain information in the study 
subject’s medical records to corroborate data collected on the CRFs. This ensures the 
validity of the study data collected and is used by the sponsor or designees to 
monitor the study. 
Data / CRF corrections and/or ambiguous data points may be resolved in person 
during monitoring visits, via data clarification forms (DCFs) provided to the site, 
and/or data queries. Findings of non-compliance and/or deviations from the 
protocol shall be reviewed with the investigator(s) and disclosed in a written 
monitoring report. The sponsor shall then either secure compliance or may 
discontinue shipments of the device to the investigator until compliance is achieved 
and/or terminate the investigator’s participation in the investigation. 
 
6 Statistical Considerations 
 
Hypothesis 
As sensitivity is a function of diseased fallopian tubes only, while specificity is a 
function of non-diseased fallopian tubes, the statistical hypotheses for sensitivity 
and specificity are considered to be independent. Each hypothesis is framed as a 1-
sided test with a type I error rate of 2.5%. 
For sensitivity, the following hypothesis will be tested: 
HNull: Sensitivity ≤ 60% versus  
HAlternative: Sensitivity > 60% 
For specificity, the following hypothesis will be tested: 
HNull: Specificity ≤ 70% versus 
HAlternative: Specificity > 70%  
 

 
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Primary Outcome 
The primary endpoint of the study is to evaluate the sensitivity and specificity of the 
cytological samples collected from the fallopian tube in determining the presence or 
absence of malignancy for fallopian tube involvement as compared to the current 
gold standard, the surgical pathology (histology) results.  
Fallopian tube involvement is defined as: 
1. Malignant cells that originated in the fallopian tube. This is detected by the 
surgical histology results from the fallopian tube. 
2. Malignant cells that have migrated to the fallopian tube. This can be detected 
by surgical histology results of the ovaries or fallopian tubes.  
 
The site’s pathology report will contain the surgical histology evaluation of the 
removed fallopian tube specimens. These results will be compared to corresponding 
results from cytologic evaluation of fallopian tube samples. Sensitivity and specificity 
will be calculated for the Cytuity™ device as compared to surgical histology of the 
ovaries and fallopian tube for fallopian tube involvement.  
 
Note that in most cases where malignant cells have migrated into the fallopian tube 
from the ovary, fallopian tube histology can be used to confirm presence of 
malignancy in the fallopian tube as outlined in #2 above. However, due to washing 
required for specimen preparation, in some cases fallopian tube histology may be 
negative although malignant cells may have been present. That is, malignant cells 
may have been washed out. Therefore, when the histology of the tube is negative, 
but the histology of the same sided ovary is positive and the cytology results of the 
fallopian tube are positive, this result will be categorized as a true positive. This 
finding will be called ‘favorable discordance’ relative to cytology results. 
 
The following formulas will be used to determine sensitivity and specificity: 
𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠=
𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝
𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝+ 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 
 
𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠=
𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛
𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛+ 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓𝑓 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 

 
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Secondary Outcomes 
The secondary endpoints will include the following: 
• Positive Predictive Value (PPV), Negative Predictive Value (NPV), and 
Diagnostic Accuracy will be calculated for Cytuity™ as compared to surgical 
histology of the ovaries and fallopian tube for fallopian tube involvement. 
• Sensitivity, specificity, PPV, NPV, and accuracy will be calculated for Cytuity™ 
as compared to surgical histology of the fallopian tube. 
• Sensitivity, specificity, PPV, NPV, and accuracy will be calculated for Cytuity™ 
as compared to surgical histology of the ovaries for epithelial malignancies.* 
• Sensitivity, specificity, PPV, NPV, and accuracy will be calculated for Cytuity™ 
as compared to surgical histology for fallopian tube involvement for subject 
level analysis. 
*Epithelial cancers, which consist of high and low-grade serous carcinomas, 
endometrioid, clear cell and mucinous subtypes make up approximately 95% of all 
ovarian cancers. 
 
Sample Size Determination 
The Cytuity™ procedure will be performed on a maximum of 150 subjects. 
Subjects will be recruited until Cytuity™ cytology results can be compared with the 
surgical histology in at least 32 subjects determined to have a malignant neoplasm 
or malignancy and 18 subjects determined by surgical histology of the excised tissues 
to be negative for malignancy.  
As this analysis will be conducted on tube level, the sample size was converted to 
look at the number of tubes that would be required. Previous data suggest that when 
1 fallopian tube is positive for malignancy, the subject’s other tube is positive about 
75% of the time, making a total correlation of 80% is a reasonable assumption. The 
following formula was used for the statistical conversion: 
Statistical conversion from subjects to fallopian tubes yields a requirement of 56 
tubes, or samples, positive for malignancy. This is because the left and right fallopian 
tube are treated as partially independent from one another in regard to the histology 
results (for example, if there is malignancy in the right tube, that does not mean that 
there is malignancy on the left). 
Based on an assumed 20% prevalence rate of (subject-level) malignancy, a sample 
size of 140 subjects (280 tubes) in which both fallopian tubes are tested is statistically 
likely to produce the minimum 56 positive tubes required. 

 
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Statistical Methods 
This trial was designed with formal statistical hypotheses for both sensitivity and 
specificity. The sample size was determined based on a fallopian tube-level (each 
tube will be considered a data point), and assuming a high correlation of 75% 
between tubes in individual subjects. Previous data suggest that when 1 fallopian 
tube is positive for malignancy, the subject’s other tube is positive about 75% of the 
time so making a total correlation of 75% is a reasonable assumption.  
Since sensitivity is a function of diseased tubes only, while specificity is a function of 
non-diseased fallopian tubes, the statistical hypotheses for sensitivity and specificity 
are considered to be independent. Each hypothesis is framed as a 1-sided test with 
a type I error rate of 2.5%. 
For sensitivity, the following hypothesis will be tested: 
HNull: Sensitivity ≤ 60% versus  
HAlternative: Sensitivity > 60% 
For specificity, the following hypothesis will be tested:  
HNull: Specificity ≤ 70% versus  
HAlternative: Specificity > 70% 
For the sample size calculation, the expected sensitivity of the Cytuity™ device is 
approximately 80% and the expected specificity is approximately 90%. Based on 
these parameters and requiring > 80% power for both hypotheses above, 32 subjects 
positive for malignancy and 18 subjects negative for malignancy are required.14
Since this is a prospective study in which it is anticipated that the number of subjects 
testing negative will far exceed subjects testing positive, the sample size calculation 
is driven by the requirements for the sensitivity hypothesis. Conversion from 
subjects to fallopian tubes yields a requirement of 56 tubes positive for cancer.15 
Based on an assumed 20% prevalence rate of (subject-level) malignancy, a sample 
size of 140 subjects (280 tubes) in which both fallopian tubes are tested is statistically 
likely to produce at least the 56 positive tubes required.  
Because the primary analysis is based on fallopian tubes, the analysis must account 
for the subject-level correlation.16 A Logistic random-effects model will be used to 
calculate the point estimates and 95% (2-sided) confidence intervals for sensitivity 
and specificity.17,18 The adjustment proposed by Obuchowski will be performed for 
comparison.13 
 Treatment of missing, spurious data, drop-outs and withdrawals 
Statistical treatment of missing, unused, invalid, or spurious data, drop outs, 
outliers, and withdrawals will be specified in the final report.  

 
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7 Data Management 
 
Case Report Forms 
This study will utilize case report forms (CRF). Each CRF page will be identified using 
the subject’s unique study identification number followed by an “L” for left tube and 
“R” for right tube.  
The investigator must review, sign, and date the CRFs as indicated on the forms; 
these responsibilities cannot be delegated to another person. It is the investigator’s 
responsibility to comply with regulatory requirements including, but not limited to, 
the maintenance of accurate, complete and current records relating to the CRFs. 
Query reports may be generated by the sponsor following data review or following 
monitoring visits. In general, data clarification forms (DCFs) and/or queries will be 
generated to make auditable additions or data corrections to the CRF. 
 
Data Management  
Data management may be handled by the sponsor or a clinical research organization 
(CRO) designee. 
The details of data entry, data review, data cleaning and data querying may be 
described in a Data Management Plan (DMP). This plan may be updated throughout 
the investigation as amended data management requirements and investigation-
specific data conventions are determined.  
 
Data Retention 
Because of the potential for errors or inaccuracies in transcribing data into CRFs, 
source documentation must be maintained in each subject’s medical chart and/or 
electronic medical record. The CRFs and source documentation must be made 
available for inspection by the monitors, as designated by the sponsor, or regulatory 
inspectors. Subject files will be created at the beginning of the study, maintained 
throughout the study and retained for two 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 needed to support a marketing application to the FDA.

 
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8 Protocol Amendments 
Investigators may not modify this protocol without obtaining written concurrence of the 
sponsor, the IRB and when required, regulatory authorities. 
9 Protocol Deviations 
The investigator agrees to conduct the investigation in accordance with this protocol. An 
investigator may not plan to deviate from this protocol without first receiving approval 
in writing from the sponsor and IRB, except when necessary to eliminate apparent 
immediate hazards to a participant.  
Deviations will be documented on CRFs. Investigators will also adhere to procedures for 
reporting investigation deviations to their IRB in accordance with their specific IRB 
reporting policies and procedures.  
Protocol deviations to the in/exclusion criteria and deviations that affect the primary 
endpoint are considered major protocol deviations.  
 
Corrective and Preventive Actions 
The sponsor or its representatives will evaluate protocol deviations during 
monitoring visits. Individual event corrections and/or corrective and preventive 
actions may be recommended at that time. In addition, deviations occurring across 
investigational sites will be reviewed by the sponsor on a periodic basis to determine 
if more global corrective and/or preventive actions may be required or a protocol 
change is warranted.  
 
Investigator Disqualification Criteria 
The sponsor reserves the right to terminate an investigator/investigational site for 
any of the following reasons: 
• Failure to secure participant informed consent prior to enrollment. 
• Failure to report serious adverse device effects within 24 hours of becoming 
aware. 
• Repeated investigational plan deviations. 
• Repeated failure to appropriately complete case report forms. 
• Failure to enroll an adequate number of participants. 
• Loss of or unaccounted investigational product. 

 
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10 Statements of Compliance 
 Investigator Responsibilities 
The principal investigator will be responsible for fulfilling the clinical study 
requirements as specified in this clinical protocol. The study center must have the 
necessary resources to comply with the requirements. Investigators will be selected 
for participation in the clinical study based on their ability to fulfill all requirements 
outlined in the investigator agreement.  
The investigator shall provide the subject ample time and opportunity to inquire 
about details of the trial and to decide whether to participate in the trial before 
informed consent is obtained and shall answer all questions about the trial to the 
satisfaction of the subject. 
 Institutional Review Board (IRB) Requirements 
No study activities will begin without documented IRB approval of the clinical 
protocol, informed consent form, and any material to be provided to potential 
subjects. The IRB has the authority and responsibility to review and approve the 
study and its conduct in accordance with local regulations. The primary purpose of 
the IRB is to protect the rights and welfare of the subjects enrolled in the clinical 
study.  
The sponsor intends to submit to a central IRB for study approval. For sites requiring 
review by a site-specific IRB, this information will be supplied to the investigators 
and the investigator is responsible for submitting those materials as needed to their 
site-specific IRB. The investigator will notify the sponsor in writing when approval 
from the IRB is granted. A letter of approval from the IRB is required, and a copy of 
this letter must be provided to sponsor. This approval should reference the name of 
the study and specific version of the clinical protocol and the informed consent 
document(s).  
The sponsor will manage annual renewals if/when a central IRB is utilized. For site-
specific IRBs, the investigator is responsible for annual renewals with the IRB or per 
the IRBs review schedule. The renewal letter based on continuing review by the IRB 
must also be provided to sponsor. 
The investigator is responsible for reporting protocol deviations and any safety 
related findings to the IRB according to their local IRB requirements. If a subject 
receives an investigational device procedure without signing an informed consent, 
the investigator must notify the IRB in writing according to the timeframes 
designated by the IRB. 

 
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11 Informed Consent Process 
Prior to the subject providing written informed consent, the investigator or his/her 
designee will inform all subjects regarding the investigational nature of the study and will 
discuss all study risks and answer all of the subject’s questions.  
The subject will be informed by the investigator that participation is voluntary, that 
refusal to participate will involve no penalty or loss of benefits to which the subject is 
otherwise entitled, and that the subject may discontinue participation (withdraw) at any 
time without penalty or loss of benefits to which the subject is otherwise entitled. The 
subject will be informed by the investigator that his/her medical records (as it relates to 
this study) will be subject to review by the sponsor's representatives and public health 
authorities, including the U.S. Food and Drug Administration (FDA). Subject identifying 
information will not be released publicly and will be available only to the sponsor and 
regulatory authorities. 
A signed, written informed consent must be obtained from the subject prior to study 
activities. The signed consent form will be provided to the subject and they will also be 
kept by the study investigator. 
When pre-approved by the sponsor, a certified translation of the informed consent form 
to another (non-English) language will be acceptable.  
12 Adverse Events 
Adverse events will be recorded on CRFs by study personnel from the time the 
hysteroscope enters the subject until study exit (defined as 24 hours post Cytuity™ use 
or discharge, whichever occurs first). If a Cytuity™ study or device related AE has occurred 
during this period, it will be followed until resolved or until 30 days post the salpingo-
oophorectomy or salpingectomy surgery. 
 Severity 
The assessment of severity is a clinical determination of the intensity of an adverse 
event. The severity assessment for a clinical adverse event should be completed by 
the investigator. These will be categorized as mild, moderate, or severe per the 
definitions noted above in this protocol. 
 Relatedness 
The potential relationship of the event to the investigational device or study 
procedure will be determined by the investigator. Relatedness will be categorized as 
not related, possibly related, or definitely related per the definitions noted above in 
this protocol. 

 
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 Reporting Requirements 
Normal post-operative incidents such as pain and nausea will not be recorded as 
adverse events. Only serious adverse events, unanticipated adverse device effects, 
investigational device and/or study related adverse events will be documented on 
case report forms. 
 Procedures for Reporting SAEs and UADEs  
In case of a serious adverse event (SAE), and all unanticipated adverse device effects 
(UADEs), the investigator should notify the sponsor within 24 hours and the 
reviewing IRB per their reporting requirements. The sponsor will assist in reporting 
to the IRB to ensure consistency of reporting. 
13 Suspension or Premature Termination of the Study 
The sponsor is responsible for the ongoing safety evaluation of the investigational 
product and should promptly notify, in writing, all investigators and of governing IRBs of 
any findings that could adversely affect the safety of participants, the trial conduct, or 
alter an approval of the trial. Should the sponsor decide that there are safety concerns 
that require immediate amendment to the protocol, informed consent, device 
instructions for use, or conduct of the study, this will be communicated to all sites and 
the governing IRBs without delay. If updates to the protocol, informed consent or device 
instructions for use can resolve the problem, updates will be made and re-submitted for 
IRB approval. 
In the event that system safety issues, poor trends, and/or an unreasonable risk to 
subjects emerges as a result of this clinical testing, the study will be terminated.  
If at any point the sponsor obtains information that suggests there is an unreasonable 
risk to subjects, the sponsor, shall as soon as possible, terminate the clinical investigation 
or the portions of the investigation presenting that risk.  
The sponsor will notify all investigators and all governing IRBs. 
14 Revision History 
Version 
Date 
Summary of Changes 
01 
06Mar2018 
• Initial release. 
02 
11Apr2018 
• Clarified language throughout 
• Removed exclusion criteria regarding the inability to 
hysteroscopically visualize fallopian tube ostia 
• Added 2nd cytopathology core lab and adjudication lab to 
review cytology cell samples, while keeping independent 
histopathology CRF completion of site pathology reports. 
• Added details related to collection of cytology samples 
and processing of cytology samples 
 

 
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03 
22Oct2019 
• Change sponsor name and contact info from nVision to 
Boston and product name from MAKO 7 to Cytuity. 
• Updated SAE and UADE definitions to match CRFs and 
FDA definitions. 
• Add pathologist names  
• Clarify the cytology slide review process to match the 
process used for all prior subjects and in use now.  This 
includes flowchart updates to match. 
• Minor updates referencing CRFs and DCFs changed to 
reflect use of eCRFs and queries in EDC 
• Minor updates to reflect that while the MAKO 7 used a 
stopcock packaged separately, the stopcock for Cytuity™ 
is packaged with the device. 
• Clarified roles of Sponsor representatives who may be 
present during cases. 
 

 
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References 
 
1.  Karlsen, MA, Sandhu, N, Høgdall, C, Christensen, IJ, Nedergaard, L, Lundvall, L, ... & Høgdall, E. V. 
(2012). Evaluation of HE4, CA125, Risk of Ovarian Malignancy Algorithm (ROMA) and Risk of 
Malignancy Index (RMI) as diagnostic tools of epithelial ovarian cancer in patients with a pelvic 
mass. Gynecologic Oncology, 127(2), 379-383. 
2.  Montagnana, M, Lippi, G, Ruzzenente, O, Bresciani, V, Danese, E, Scevarolli, S, Salvagno, GL, 
Giudici, S, Franchi, M and Guidi, GC. (2009). The utility of serum Human Epididymis Protein 4 
(HE4) in patients with a pelvic mass. Journal of Clinical Laboratory Analysis, 23, 331–335 
 
3.  Yang, Z, Luo, Z, Zhao, B, Zhang, W, Zhang, J, Li, Z, & Li, L. (2013). Diagnosis and preoperative 
predictive value of serum HE4 Concentrations for optimal debulking in epithelial ovarian cancer. 
Oncology Letters, 6(1), 28-34. 
4.  Havrilesky, LJ, Whitehead, CM, Rubatt, JM, Cheek, RL, Groelke, J, He, Q., ... & Berchuck, A. 
(2008). Evaluation of biomarker panels for early stage ovarian cancer detection and monitoring 
for disease recurrence. Gynecologic Oncology, 110(3), 374-382. 
5.  Moore, RG, Brown, AK, Miller, MC, Skates, S, Allard, WJ, Verch, T, ... & Bast, RC. (2008). The use 
of multiple novel tumor biomarkers for the detection of ovarian carcinoma in patients with a 
pelvic mass. Gynecologic Oncology, 108(2), 402-408. 
6.  Jacob, F, Meier, M, Caduff, R, Goldstein, D, Pochechueva, T, Hacker, N, ... & Heinzelmann-
Schwarz, V. (2011). No benefit from combining HE4 and CA125 as ovarian tumor markers in a 
clinical setting. Gynecologic Oncology, 121(3), 487-491. 
7.  Partheen, K, Kristjansdottir, B, & Sundfeldt, K. (2011). Evaluation of ovarian cancer biomarkers 
HE4 and CA-125 in women presenting with a suspicious cystic ovarian mass. Journal of 
Gynecologic Oncology, 22(4), 244-252 
8.  Visintin, I, Feng, Z, Longton, G, Ward, DC, Alvero, AB, Lai, Y, ... & Mor, G. (2008). Diagnostic 
markers for early detection of ovarian cancer. Clinical Cancer Research, 14(4), 1065-1072. 
9.  Su, F, Lang, J, Kumar, A, Ng, C, Hsieh, B, Suchard, MA, ... & Farias-Eisner, R. (2007). Validation of 
candidate serum ovarian cancer biomarkers for early detection. Biomarker Insights, 2(369). 
10.  Andersen, MR, Goff, BA, Lowe, KA, Scholler, N, Bergan, L, Drescher, CW, ... & Urban, N. (2010). 
Use of a symptom index, CA125, and HE4 to predict ovarian cancer. Gynecologic Oncology, 116(3), 
378-383. 
11.  Tan SY, Tatsumura Y. George Papanicolaou (1883–1962): Discoverer of the Pap smear. Singapore 
Medical Journal. 2015;56(10):586-587. 
12.  Lum D, Guido R, Rodriguez E, Lee E, Mansuria S, D’Ambrosio L, and Austin R, MD. (2014). Brush 
cytology of the fallopian tube and implications in ovarian cancer screening. Journal of Minimally 
Invasive Gynecology, 21(5), 851 – 856. 
13.  ISO 14971:2007 Medical devices -- Application of risk management to medical devices 
14.  Zhou XH, Obuchowski NA, McClish DK (2011). Statistical methods in diagnostic medicine, second 
edition. Hoboken, New Jersey: John Wiley & Sons, Inc. 
15.  Obuchowski NA. Nonparametric analysis of clustered ROC curve data. Biometrics. 1997 
Jun;53(2):567-78. 
16.  Genders TS, Spronk S, Stijnen T, Steyerberg EW, Lesaffre E, Hunink MG. Methods for calculating 
sensitivity and specificity of clustered data: a tutorial. Radiology. 2012 Dec;265(3):910-6. doi: 
10.1148/radiol.12120509. Epub 2012 Oct 23. 
17.  Coughlin SS, Trock B, Criqui MH, Pickle LW, Browner D, Tefft MC. The logistic modeling of 
sensitivity, specificity, and predictive value of a diagnostic test. J Clin Epidemiol. 1992 
Jan;45(1):1-7. 
18.  Ying, Gui-Shuang & D Chengcheng Liu, Ph. (2006). Statistical analysis of clustered data using SAS 
System. NorthEast SAS Users Group (NESUG) Proceedings.