A CLinical Study to Evaluate the Safety And Effectiveness of the CeRene DevIce to Treat HeavY Menstrual Bleeding
Phase: NA
Conditions: Menorrhagia
Sponsor: Channel Medsystems

NCT Number: NCT02842736

 
Clarity Clinical Study Protocol, CIP-0101, Rev. K 
 
 
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STUDY ACKNOWLEDGMENT 
 
Investigator's Statement 
I have read and understand the foregoing protocol entitled: “A CLinical Study to Evaluate 
the Safety And Effectiveness of the CeRene DevIce to Treat HeavY Menstrual Bleeding 
(CLARITY)” and all corresponding amendments and agree to conduct the study as 
outlined herein. 
 
Confidentiality 
I understand that all information not previously published concerning this study and 
Channel Medsystems devices is confidential. The confidential information includes, but 
is not limited to, the study protocol, case report forms, and study data. I agree not to 
publically disclose such confidential information without first acquiring written permission 
from Channel Medsystems. 
 
Ethics Committee / Investigational Review Board Approval 
I acknowledge that I will not begin enrolling subjects into this study before obtaining 
approval from my local ethics committee or investigational review board. 
 
Deviations 
I understand my obligation to complete this study with full adherence to the written 
protocol, informed consent, and Instructions for Use. I understand that deviations from the 
protocol impair the ability to interpret the study data. Unless required to protect the health 
and/or safety of the individual subject, I will not knowingly deviate from the protocol without 
first obtaining written permission from the study sponsor. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator's Name (please print) 
 
 
 
 
 
 
 
 
 
Investigator's Signature 
 
 
 
 
 
Date 
 
 

 
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SIGNATURE OF THE SPONSOR’S MEDICALLY RESPONSIBLE PERSON 
 
 
 
The Study Medical Expert agrees to the content of the clinical study protocol as 
presented. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name (please print) 
 
 
 
 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
 
 

 
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SIGNATURE OF STUDY PRINCIPAL INVESTIGATOR 
 
 
 
The Study Principal Investigator agrees to the content of the final clinical study protocol 
as presented. 
 
 
 
 
NOT APPLICABLE; THERE IS NO STUDY PRINCIPAL INVESTIGATOR 
 
 
 
 
 
 
 
 
 
 
, MD 
Name (please print) 
 
 
 
NOT APPLICABLE 
 
 
 
 
 
 
Signature 
 
 
 
 
 
 
 
Date 
 
 
 
 
 
Hospital or Medical Center Affiliation and Address: 
 
NOT APPLICABLE 
 
 
 
 
 
 

 
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Table of Contents 
 
1 
INTRODUCTION .............................................................................................................. 11 
1.1 
BACKGROUND ON ABLATION TECHNIQUES ....................................................................... 11 
1.2 
DESCRIPTION OF THE CERENE DEVICE ............................................................................ 13 
1.3 
REPORT OF PRIOR INVESTIGATIONS ................................................................................ 15 
2 
STUDY DESIGN .............................................................................................................. 17 
2.1 
STUDY OBJECTIVES ........................................................................................................ 17 
2.2 
PRIMARY SAFETY ENDPOINT............................................................................................ 17 
2.3 
PRIMARY EFFECTIVENESS ENDPOINT ............................................................................... 17 
2.4 
ADDITIONAL EVALUATIONS FOLLOWING ABLATION TREATMENT ......................................... 17 
3 
SUBJECT ELIGIBILITY ................................................................................................... 18 
3.1 
INCLUSION CRITERIA ...................................................................................................... 18 
3.2 
EXCLUSION CRITERIA ..................................................................................................... 18 
4 
SUCCESS CRITERIA ...................................................................................................... 20 
4.1 
STATISTICAL ANALYSIS PLAN SUMMARY .......................................................................... 20 
4.1.1 Primary Effectiveness Endpoint ......................................................................................... 20 
4.1.2 Primary Safety Endpoint...................................................................................................... 21 
4.1.3 Sample Size .......................................................................................................................... 21 
4.1.4 Study Populations ................................................................................................................ 21 
4.1.5 Poolability .............................................................................................................................. 21 
4.1.6 Adaptive Design Interim Analysis ...................................................................................... 22 
4.1.7 Patient Accountability and Missing Data........................................................................... 22 
4.1.8 Statistical Method ................................................................................................................. 23 
5 
STUDY METHODS .......................................................................................................... 24 
5.1 
INSTITUTIONAL REVIEW BOARD / ETHICS COMMITTEE APPROVAL ..................................... 24 
5.2 
INFORMED CONSENT ...................................................................................................... 25 
5.3 
STUDY IDENTIFICATION NUMBER ..................................................................................... 25 
5.4 
INVESTIGATIONAL DEVICE TRAINING ................................................................................ 25 
5.5 
SAFETY DATA REVIEW .................................................................................................... 26 
5.6 
SUBJECT EXIT ................................................................................................................ 26 
5.7 
PREMATURE STUDY TERMINATION .................................................................................. 26 
6 
SCHEDULE OF STUDY PROCEDURES AND ASSESSMENTS ................................... 27 
6.1 
SUBJECT RECRUITMENT AND SCREENING ....................................................................... 28 
6.1.1 Subject Recruitment ............................................................................................................. 28 
6.1.2 Screening Evaluations ......................................................................................................... 28 
6.2 
PBLAC DIARY: SCREENING AND FOLLOW-UP REPORTING ............................................... 29 

 
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6.3 
ENDOMETRIAL THINNING................................................................................................. 31 
6.4 
CERENE ABLATION TREATMENT ...................................................................................... 31 
6.4.1 Subject Preparation for Treatment .................................................................................... 31 
6.4.2 Ablation Treatment ............................................................................................................... 31 
6.5 
POST-TREATMENT THROUGH DISCHARGE ....................................................................... 32 
6.6 
DAY 1 POST TREATMENT (+3 DAYS) ................................................................................ 32 
6.7 
WEEK 2 POST TREATMENT (+ 2 WEEKS) .......................................................................... 32 
6.8 
MONTH 3 POST TREATMENT (± 4 WEEKS) ........................................................................ 33 
6.9 
MONTH 6 POST TREATMENT (± 4 WEEKS) ........................................................................ 33 
6.10 MONTH 12 POST TREATMENT (± 4 WEEKS) ...................................................................... 33 
6.11 MONTH 24 POST TREATMENT (± 4 WEEKS) ...................................................................... 33 
6.12 MONTH 36 POST TREATMENT (± 4 WEEKS) / SUBJECT EXIT ............................................. 34 
7 
ADVERSE EVENT REPORTS ........................................................................................ 34 
8 
RISKS AND BENEFITS ................................................................................................... 38 
8.1 
POTENTIAL RISKS TO THE SUBJECT ................................................................................ 38 
8.2 
INSURANCE COVERAGE .................................................................................................. 40 
8.3 
POTENTIAL BENEFITS TO THE SUBJECT ........................................................................... 40 
9 
STUDY MONITORING ..................................................................................................... 40 
9.1 
RESPONSIBILITIES OF THE SPONSOR ............................................................................... 41 
9.2 
RESPONSIBILITIES OF THE INVESTIGATOR ........................................................................ 41 
10 
RECORD KEEPING AND REPORT REQUIREMENTS .................................................. 42 
10.1 SUBJECT CONFIDENTIALITY ............................................................................................ 42 
10.2 PROTOCOL DEVIATIONS .................................................................................................. 42 
10.3 INVESTIGATOR REPORTS ................................................................................................ 42 
10.4 RECORD RETENTION ...................................................................................................... 43 
11 
REFERENCES ................................................................................................................. 44 
 
 
 
 

 
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STUDY SYNOPSIS 
INTENDED USE 
The Cerene Cryotherapy Device (Cerene) is intended to ablate the 
endometrial lining of the uterus in premenopausal women with heavy 
menstrual bleeding due to benign causes for whom child bearing is 
complete. 
STUDY 
PURPOSE 
The purpose of this study is to evaluate the safety and effectiveness of 
the Cerene Device. 
STUDY DESIGN 
This is a prospective, multi-center, single-arm, open-label, non-
randomized pivotal study. The Cerene Device will be used to treat heavy 
menstrual bleeding due to benign causes in women who meet the 
inclusion and exclusion criteria.  
Subjects will be assessed following ablation treatment through Month 12 
for all study endpoints and at Month 24 and 36 for any additional medical 
or surgical interventions needed to manage continued heavy menstrual 
bleeding.   
NUMBER OF 
SUBJECTS 
242 subjects will undergo Cerene cryoablation treatments. 
STUDY 
CENTERS 
Up to 20 centers in 3 countries  
STUDY 
EVALUATIONS 
Primary safety endpoint: 
 
Incidence of serious adverse events and serious device-related 
adverse events at 12 months 
Primary effectiveness endpoint: 
 
Reduction in menstrual bleeding at 12 months; success is defined 
as a score of  ≤ 75 measured using a pictorial blood loss 
assessment chart (PBLAC) 
Additional evaluations: 
 
Amenorrhea rate at Month 12 
 
Subject-reported peri-procedural pain experience 
 
Evaluation of dysmenorrhea at Month 12 
 
Quality of Life outcome at Month 3, 6, and 12: using the 
Menorrhagia Impact Questionnaire (MIQ) and the Premenstrual 
Symptoms Impact Survey (PMSIS)  
 
Month 24 and 36 telephone contact or office visit to include an 
assessment of gynecologic adverse events, additional medical or 
surgical interventions for continued heavy menstrual bleeding, QoL 
measurements by MIQ and PMSIS, type of contraception and 
compliance, and pregnancy query 
 
Evaluation of uterine access and healing at Month 12 

 
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STUDY SYNOPSIS 
STUDY 
DURATION 
Total Duration: 
3 years after last subject treated 
STUDY 
POPULATION 
Adult pre-menopausal female subjects with heavy menstrual bleeding 
who meet the inclusion and exclusion criteria 
INCLUSION 
CRITERIA 
1. Refractory heavy menstrual bleeding with no definable organic cause 
2. Female subject age 25 to 50 years, inclusive 
3. Endometrial cavity measurements within the following parameters: 
 
Sounded length of uterine cavity (exocervix to fundus) no greater 
than 10 cm; AND  
 
Endometrial cavity length (internal os to fundus) must be 
between 2.5 and 6.5 cm, inclusive 
4. Myometrial thickness of at least 10 mm 
5. Menstrual blood loss with a PBLAC score of ≥ 150, within 3 months of 
informed consent, for: 
Two baseline cycles; OR 
One baseline cycle in a woman who has at least 3 prior months 
documented failed medical therapy; or has a contraindication to 
medical therapy; or cannot tolerate medical therapy; and/or was 
offered and declined medical therapy 
6. Premenopausal confirmed by FSH measurement ≤ 30 IU/L when age is 
> 40 years 
7. Agrees to use a reliable form of non-hormonal contraception following 
ablation treatment up to the 12-month follow-up visit unless the subject 
is currently using a hormonal birth control method, has been on said 
method for ≥ 3 months prior to informed consent, and agrees to remain 
on the same hormonal regimen up to the 12-month follow-up visit. 
8. Provides written informed consent using a form that has been approved 
by the reviewing IRB/EC 
9. Agrees to follow-up exams and data collection requirements 
10. Demonstrates an understanding of how to record menstrual blood loss 
using a menstrual pictogram 
11. Has predictable, cyclic menstrual cycles  
EXCLUSION 
CRITERIA 
1. Pregnant or has a desire to conceive 
2. Endometrial hyperplasia as confirmed by histology 
3. Active endometritis 
4. Active pelvic inflammatory disease 
5. Active sexually transmitted disease (STD) 
6. Presence of bacteremia, sepsis, or other active systemic infection 
 
7. Active infection of the genitals, vagina, cervix, or uterus 

 
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STUDY SYNOPSIS 
8. Known/suspected abdominal, pelvic, or gynecological malignancy 
within the past 5 years  
9. Known clotting defects or bleeding disorders  
10. Abnormal cytology on Human papillomavirus (HPV) testing not treated 
according to local standards. 
11. Prior uterine surgery that interrupts the integrity of the uterine wall (e.g., 
transmural myomectomy or classical cesarean section).  
12. Previous low transverse cesarean section where the myometrial wall 
thickness at the thinnest section of the scar is less than 10 mm, 
measured by Saline Infused Sonohysterogram 
13. Previous endometrial ablation procedure 
14. Clinically significant adenomyosis indicated by subject complaints, 
imaging, or clinician’s judgment 
15. Presence of an implantable contraceptive device (e.g. Essure™ or 
Adiana™) 
16. Currently on medications that could thin the myometrial muscle, such 
as long-term steroid use (except inhaler or nasal therapy for asthma) 
17. Currently on anticoagulants 
18. Abnormal or obstructed cavity, specifically: 
a) Septate or bicornuate uterus or other congenital malformation of the 
uterine cavity 
b) Polyps larger than 1 cm (in largest dimension) or which are likely to 
be the cause of the subject’s heavy menstrual bleeding 
c) Any submucosal myoma  
d) Any myoma that distort(s) the endometrial cavity 
e) Any myoma, polyp configuration, uterine position, and/or uterine 
anomaly that, in the opinion of the investigator, 
i. obstructs or hinders treatment access to the endometrial cavity 
ii. prevents deployment of the device 
iii. and/or is contraindicated for use of the investigational device 
19. Currently using an intrauterine device (IUD), including Mirena™ device, 
and unwilling to remove the IUD  
20. Post-partum ≤ 6-months 
21. Considering participation in a research study of an investigational drug 
or device that would begin during the course of this investigational study 
22. Any general health or mental, or other situation or condition which, in 
the opinion of the Investigator, could represent an increased risk for the 
subject or impact the subject’s ability to comply with protocol 
requirements 
 
 

 
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LIST OF ABBREVIATIONS  
 
AE 
Adverse Event 
CRF 
Case Report Form 
EA 
Endometrial Ablation 
EC 
Ethics Committee 
EEC 
Endometrial Echo Complex 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
FSH 
Follicle-Stimulating Hormone 
GLP 
Good Laboratory Practices 
HMB 
Heavy Menstrual Bleeding 
IC 
Informed Consent 
IFU  
Instructions for Use 
IRB 
Institutional Review Board 
MIQ 
Menorrhagia Impact Questionnaire 
NREA 
Non-Resectoscopic Endometrial Ablation 
PBLAC  Pictorial Blood Loss Assessment Chart 
QOL 
Quality of Life 
REA 
Resectoscopic Endometrial Ablation 
SAE 
Serious Adverse Event 
SADE 
Serious Adverse Device Event 
STD 
Sexually transmitted disease 
SIS 
Saline Infused Sonohysterography 
SOP 
Standard Operating Procedure 
UADE 
Unanticipated Adverse Device Effect 
 
 

 
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1 
Introduction 
1.1 
Background on Ablation Techniques 
Historically, therapy with hormonal or non-hormonal medications and surgical procedures, 
including supracervical or total hysterectomy, have been the mainstay of treatment for the 
spectrum of disorders that manifest in heavy menstrual bleeding (HMB).  Although the minimally 
invasive procedures that are collectively known as endometrial ablation (EA) were originally 
developed more than 100 years ago (Fritsch 1898), and further evolved in the early and mid-20th 
century (Bardenheuer 1937, Cahan and Brockunier 1967, Droegemueller, Greer et al. 1970, 
Droegemueller, Greer et al. 1971), it is only in the past 25 years that they have been practicably 
available to at least selected women experiencing the symptom of HMB. 
 
Endometrial ablation has been classified as “first generation” and “second generation,” but 
confusion regarding just what was “first” and what was “second” has led to a more descriptively 
accurate classification of resectoscopic and non-resectoscopic technique.  Whereas the earliest 
non-resectoscopic techniques were introduced in the late 19th (Fritsch 1898) and early 20th 
century (Bardenheuer 1937), intrauterine application of the urological resectoscope introduced in 
the late 1980s was responsible for the widespread adoption of endometrial ablation as a viable 
therapeutic procedure (Vancaillie 1989).  Resectoscopic endometrial ablation (REA) requires the 
use of a modified urological resectoscope that includes an endoscope (a hysteroscope), a 
mechanism for instilling and removing fluid distending media, and a radiofrequency electrode 
shaped as a barrel, ball ("rollerball") or wire loop that is used to remove or destroy the endometrial 
lining.  These techniques typically require an anesthesiologist to administer general or regional 
anesthesia in the context of an institutional operating room.  Potential risks of these procedures 
include cervical laceration, uterine perforation and subsequent sequelae, and fluid overload that 
may result in heart failure and pulmonary edema, and, if electrolyte-poor solutions are used, 
hyponatremia and related encephalopathy, an event that contributes to the mortality associated 
with these procedures (Ayus, Wheeler et al. 1992, Istre, Skajaa et al. 1992, Baggish, Brill et al. 
1993, Corson 1994, Overton, Hargreaves et al. 1997, Munro 2010).  Furthermore, it is evident 
that both the clinical outcome and the incidence of these complications are directly related to the 
training and skill of the surgeon (Overton, Hargreaves et al. 1997, Pooley, Ewen et al. 1998). 
 
Non-resectoscopic endometrial ablation (NREA) techniques use one of a number of approaches 
to destroy the endometrium but do not require the use of a resectoscope and the accompanying 
large volumes of fluid, thereby eliminating the risks of fluid overload and resulting fluid and 
electrolyte imbalances.  In addition, NREA techniques typically are automated and/or provide 
surgeon feedback to at least some degree and, while they can’t be perceived to be “global” in 
impact, the clinical outcome is less dependent upon the skill and training of the surgeon.  
Furthermore, and to some degree, depending on the technique, they can be performed in the 
context of an office procedure room, potentially using local anesthesia.  
 
In 1997, the United States Food and Drug Administration approved the first global endometrial 
ablation (GEA) device (Meyer, Walsh et al. 1998) designed to treat heavy menstrual bleeding, in 
selected women with normal endometrial cavities.  The GYNECARE THERMACHOICE® Uterine 

 
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Balloon Therapy System (Ethicon, Inc., Somerville, NJ) comprises a 5.5 mm outside diameter 
(OD) balloon-tipped catheter that is blindly positioned in the endometrial cavity and then filled with 
fluid that is subsequently heated by a remotely located controller “box” to 188°F (87°C) for eight 
minutes.  In 2001, the FDA approved the other devices.  The Hydro ThermAblator® System 
(Boston Scientific Corp., Natick, MA) is a 7.8 mm OD sheath that is used to deliver saline into the 
endometrial cavity under hysteroscopic guidance (Corson 2001).  Upon confirmation of proper 
positioning, the remotely located controller system heats the saline solution until it reaches the 
target temperature of 93°C, which it holds for 10 minutes before the system is cooled. The 
NovaSure® Impedance Controlled Endometrial Ablation System (Hologic, Inc., Bedford, MA) is a 
7.2 mm probe that, following blind positioning in the endometrial cavity, deploys a triangular 
bipolar mesh electrode (Cooper, Gimpelson et al. 2002).  Following passage of a gas-based 
confirmation test, the system is activated by the remotely located controller system.  When the 
combination of coagulation and desiccation results in a threshold local impedance of 50 ohms, 
the machine turns off, generally following about 90 seconds of therapy.  The Her Option® Office 
Cryoablation Therapy (CooperSurgical, Inc., Trumbull, CT) uses a 5.5 mm OD cryoprobe that is 
blindly positioned in the endometrial cavity, but which can, in many instances, be confirmed by 
ultrasound (Duleba, Heppard et al. 2003).  When activated by the remotely located controller unit, 
the system is capable of producing temperatures of negative 148°F (minus 100°C) to freeze the 
uterine lining.  This device is used with ultrasound guidance to monitor the ablation procedure 
with treatment times typically ranging from 10 – 20 minutes.  In 2015, the FDA approved the 
Minerva Endometrial Ablation System (Minerva Surgical, Inc., Redwood City, CA) which uses a 
bipolar 480 kHz RF power generator and controller for endometrial ablation.  The handpiece 
contains circulating argon gas and is blindly positioned in the endometrial cavity.  Treatment is 
achieved during a two minute procedure from heat conduction through the distal end of the 
handpiece and a small amount of bi-polar RF current travelling through the target tissue (U. S. 
Food and Drug Administration, Minerva™ SSED, 2015).  (U. S. Food and Drug Administration, 
Minerva™ SSED, 2015).  Collectively and individually, these NREA techniques have been 
associated with fewer severe adverse events than was the experience with REA (Lethaby, Hickey 
et al. 2009). 
 
Channel Medsystems, Inc. (California, USA) has developed the Cerene Cryotherapy Device 
(Cerene Device) to address the unmet clinical need for a totally handheld device with a narrow 
diameter probe and fast treatment time that could also be used in the office setting with limited 
requirements for sedation or anesthesia (deep sedation).  The distally-located cavity-conforming 
liner is filled with nitrous oxide from the device handle, which freezes and ablates the adjacent 
endometrium.  The ablation procedure should be less painful than those performed with the 
hyperthermic (heat-based) ablation techniques due to the anesthetic effect of the cryogenic fluid 
on nerves in the uterine tissue (Evans 1981).  As well, the tissue healing response to cryoablation 
is favorable, has been well documented (Droegemueller, Makowski et al. 1971, Schantz and 
Thormann 1984, Chua, Chou et al. 2007, Baust, Gage et al. 2009), and may preserve access to 
the endometrial cavity in subsequent years.  By minimizing the development of synechiae, or 
adhesions, that make sampling of the endometrium difficult (Sharp 2012), treatment with the 
Cerene Device may reduce the risk of impaired cavity access. 
 

 
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The Cerene Device is intended to reduce treatment time and to deliver consistent results that are 
less dependent on physician skill levels.  The Cerene Device is also designed to tailor the ablation 
to the endometrial cavity being treated, while delivering consistent ablation depths throughout the 
cavity and simultaneously reducing ablation depth in thinner areas of the myometrium, particularly 
the cornual regions and the lower segment.  The device is designed as an alternative to 
hysterectomy, aiming to achieve the desired reduction in heavy menstrual bleeding while reducing 
the risks associated with major surgery, such as illness or death.  This device requires no incision 
and, therefore, is minimally invasive. 
 
This multi-center, international, single arm pivotal study will be conducted under all applicable 
local and country regulatory requirements and guidance.  The objective of the study is to 
demonstrate the safety and effectiveness of the Cerene Device in a population of subjects with 
heavy menstrual bleeding due to benign causes.   
 
1.2 
Description of the Cerene Device 
Channel Medsystems’ Cerene Device (Figure 1) is handheld and designed to safely treat heavy 
menstrual bleeding (HMB).  
The device uses 
cryothermic energy to achieve uniform ablation depths 
 throughout the uterine cavity  
  The cryothermic energy is provided by a liquid-to-gas 
phase change of nitrous oxide (N2O)
  During the 2½ minute treatment 
cycle, liquid N2O (originating from a small cylinder located in the device handle) flows through a 
Nitinol tube and into an infusion lumen with multiple jets.  This liquid N2O is infused into an ultra-
thin
 polyurethane liner (balloon) and phase changes into gas.  The gaseous N2O is 
exhausted through a flexible tube exiting the bottom of the handle.  
 
 
s a result, the 
Cerene Device is able to treat uterine cavities ranging in length between 2.5 and 6.5 cm.  
 
 
 
 
 
 
 

 
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Figure 1: Cerene Device 
 
 
 
The status and sequential operating instructions are displayed on the device’s LCD screen.  After 
removal from sterile packaging, a twist ring is rotated to open the N2O valve and turn on the 
device.  The user is then prompted to press the button and insert the device to the fundus.  The 
small diameter of the device 
 is designed to facilitate insertion and minimize the 
need for dilation.  After insertion, the device prompts the user to partially retract the sheath and 
press the button a second time to slowly inflate and deploy the distal portion of the liner.  Once 
the preset pressure is reached, the device prompts the user to retract the sheath to the full cavity 
length (shown on the LCD).  A third button press initiates treatment.  The uterine cavity is gently 
pressurized 
 with filtered air, deflated and re-pressurized a second time.  A final 
liner leak detection test is completed and then the N2O flow is automatically initiated.  At any time, 
the user can pause or stop the procedure.  After 2½ minutes, N2O flow is stopped and the user is 
prompted to vent the remaining N2O.  Vacuum is initiated within the liner to expedite device 
removal.  After use, the entire device is disposed per local practice. 
 
Numerous features ensure the safety of the Cerene Device.  
 
 
 
 
 

 
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1.3 
Report of Prior Investigations 
Channel Medsystems conducted multiple studies during the development of the Cerene 
Cryotherapy Device.  These included extirpated, peri-hysterectomy, pre-hysterectomy trials.  In 
addition, a feasibility study was conducted that included the intended population of subjects for a 
pivotal trial.  These trials were designed to establish the final device configuration and assure that 
the device would deliver the intended energy in a safe and effective manner in a clinical setting. 
 
The feasibility study was a prospective, single-arm, multi-center study to evaluate the safety and 
potential effectiveness of the cryotherapy device in reducing heavy menstrual bleeding and to 
define parameters for a future pivotal clinical trial that would support a pre-market approval 
application to the U.S. Food and Drug Administration (FDA).  Three (3) Canadian clinical sites 
participated 
 
 forty (40) subjects underwent endometrial cryotherapy treatment.  Thirty 
seven (37) evaluable subjects completed six (6) months of follow-up.  Twenty-four (24) of the 37 
subjects consented to and completed additional follow up visits at nine (9) months and twelve (12) 
months post treatment. 
 
The primary safety endpoint was the incidence and severity of adverse events at 6 months.  The 
primary efficacy endpoint was the reduction in menstrual bleeding at 6 months defined as a score 
of < 75 using a Pictorial Blood Loss Assessment Chart (PBLAC).   
 
The feasibility protocol included subjects with a broad range of uterine cavity measurements: 
uterine sound measurement of < 14 cm and endometrial cavity length (internal os to fundus) 
between ≥ 2.5 cm and ≤ 8.0 cm.  A reduction in menstrual bleeding was demonstrated in the 
majority of evaluable subjects treated.  At baseline, all subjects had a PBLAC score of ≥ 150 and 
at the 6 month visit, 75% of evaluable subjects had a PBLAC score of ≤ 75.   
 
In the proposed CLARITY pivotal study, the effectiveness of the Channel Medsystems 
Cryotherapy device will be compared to an FDA established objective performance criterion 
(OPC).  The OPC approach utilizes data from the pivotal clinical trials of five approved endometrial 
ablation systems that included similar patient populations.  In general, the endometrial ablation 
systems that comprise the OPC are indicated for a uterine sound measurement of ≤10 cm.  
Therefore, Channel Medsystems tabulated the PBLAC data from the feasibility study for subjects 
with a uterine sound measurement between 6 and 10 cm, inclusive, and endometrial cavity length 
≥ 2.5 cm to ≤ 6.5 cm.  At the 6 month visit, 81% of this group of subjects had a PBLAC score of ≤ 

 
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75.  The proposed pivotal study of the Channel Medsystems cryotherapy device will include only 
subjects with a uterine sound measurement of ≤ 10 cm, consistent with currently marketed 
endometrial ablation systems. 
 
The incidence of adverse events and serious adverse events in the feasibility study was very low.  
 
 
 
 There were no unanticipated adverse device effects or 
unanticipated adverse events. 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
The results of this feasibility study provide reasonable assurance that endometrial ablation with 
the Channel Medsystems cryotherapy device is safe, well tolerated, and effective in reducing 
heavy menstrual bleeding, establish tentative effectiveness rates for use in sample size 
calculations, and support initiation of this pivotal clinical study. 

 
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2 
Study Design 
This is a multi-center, international, single arm study to evaluate the safety and effectiveness of 
the Cerene Device.  Subjects must satisfy all eligibility criteria.  Approximately 242 women with 
heavy menstrual bleeding, with no definable organic cause, will be treated.   
 
 
 
 
 
 
 
  
 
Post ablation treatment, subject follow-up will include assessments at day 1, week 2, months 3, 
6, 12, 24, and 36.  Subjects will be assessed through month 12 post ablation treatment for all 
safety and effectiveness endpoints and at months 24 and 36 for any additional medical or surgical 
interventions that were needed to manage continued heavy menstrual bleeding.   
 
2.1 
Study Objectives 
The purpose of this study is to evaluate the safety and effectiveness of the Cerene Device. 
 
2.2 
Primary safety endpoint  
The incidence of serious adverse events and serious device-related adverse events at twelve (12) 
months will be evaluated. 
 
2.3 
Primary effectiveness endpoint  
The reduction in heavy menstrual bleeding will be evaluated.  Success is defined as a reduction 
in menstrual bleeding at 12 months to ≤ 75 as measured by a Pictorial Blood Loss Assessment 
Chart (PBLAC). 
 
2.4 
Additional evaluations following Ablation treatment 
 
Amenorrhea rate at Month 12 
 
Subject-reported peri-procedural pain experience 
 
Evaluation of dysmenorrhea at Month12 
 
Quality of Life outcomes at Month 3, 6, and 12: using the Menorrhagia Impact Questionnaire 
(MIQ) and the Premenstrual Symptoms Impact Survey (PMSIS)  
 
Month 24 and 36 telephone contact or office visit to include an assessment of gynecologic 
adverse events, additional medical or surgical interventions for continued heavy menstrual 
bleeding, QoL measurements by MIQ and PMSIS, contraception type and compliance, and 
pregnancy query 

 
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 
Evaluation of uterine access and healing at Month 12 
3 
Subject Eligibility 
Subjects who meet all inclusion and exclusion eligibility criteria and agree to participate in the 
study will be treated. 
 
3.1 
Inclusion Criteria 
A subject must meet all of the following inclusion criteria prior to ablation treatment: 
1. 
Refractory heavy menstrual bleeding with no definable organic cause 
2. 
Female subject age 25 to 50 years, inclusive 
3. 
Endometrial cavity measurements within the following parameters: 
 
Sounded length of uterine cavity (exocervix to fundus) no greater than 10 cm; AND  
 
Endometrial cavity length (internal os to fundus) must be between 2.5 and 6.5 cm, 
inclusive 
4. 
Myometrial thickness of at least 10 mm 
5. 
Menstrual blood loss with a PBLAC score of ≥ 150, within 3 months of informed consent, 
for: 
Two baseline cycles; OR 
One baseline cycle in a woman who has at least 3 prior months documented failed medical 
therapy; or has a contraindication to medical therapy; or cannot tolerate medical 
therapy; and/or was offered and declined medical therapy 
6. 
Premenopausal confirmed by FSH measurement ≤ 30 IU/L when age is > 40 years 
7. 
Agrees to use a reliable form of non-hormonal contraception following ablation treatment 
up to the 12-month follow-up visit unless the subject is currently using a hormonal birth 
control method, has been on said method for ≥ 3 months prior to informed consent, and 
agrees to remain on the same hormonal regimen up to the 12-month follow-up visit. 
8. 
Provides written informed consent using a form that has been approved by the reviewing 
IRB/EC 
9. 
Agrees to follow-up exams and data collection requirements 
10. 
Demonstrates an understanding of how to record menstrual blood loss using a menstrual 
pictogram 
11. 
Has predictable, cyclic menstrual cycles  
 
3.2 
Exclusion Criteria 
A subject must NOT meet any of the following exclusion criteria prior to ablation treatment: 
1. 
Pregnant or has a desire to conceive 
2. 
Endometrial hyperplasia as confirmed by histology 
3. 
Active endometritis 

 
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4. 
Active pelvic inflammatory disease 
5. 
Active sexually transmitted disease (STD) 
6. 
Presence of bacteremia, sepsis, or other active systemic infection 
7. 
Active infection of the genitals, vagina, cervix, uterus 
8. 
Known/suspected abdominal, pelvic, or gynecological malignancy within the past 5 years  
9. 
Known clotting defects or bleeding disorders  
10. 
Abnormal cytology on HPV testing not treated according to local standards  
11. 
Prior uterine surgery that interrupts the integrity of the uterine wall (e.g., transmural 
myomectomy or classical cesarean section).   
12. 
Previous low transverse cesarean section where the myometrial wall thickness at the 
thinnest section of the scar is less than 10 mm, measured by Saline Infused 
Sonohysterogram 
13. 
Previous endometrial ablation procedure 
14. 
Clinically significant adenomyosis indicated by subject complaints, imaging, or clinician’s 
judgment 
15. 
Presence of an implantable contraceptive device (e.g. Essure™ or Adiana™) 
16. 
Currently on medications that could thin the myometrial muscle, such as long-term steroid 
use (except inhaler or nasal therapy for asthma) 
17. 
Currently on anticoagulants 
18. 
Abnormal or obstructed cavity, specifically: 
a. Septate or bicornuate uterus or other congenital malformation of the uterine cavity 
b. Polyps larger than 1 cm (in largest dimension) or which are likely to be the cause of 
the subject’s heavy menstrual bleeding 
c. Any submucosal myoma  
d. Any myoma that distort(s) the endometrial cavity 
e. Any myoma, polyp configuration, uterine position, and/or uterine anomaly that, in the 
opinion of the investigator, 
i. 
obstructs or hinders treatment access to the endometrial cavity 
ii. 
prevents deployment of the device 
iii. 
and/or is contraindicated for use of the investigational device 
19. 
Currently using an intrauterine device (IUD), including Mirena™ device, and unwilling to 
remove the IUD 
20. 
Post-partum ≤ 6-months 
21. 
Considering participation in a research study of an investigational drug or device that 
would begin during the course of this investigational study 
22. 
Any general health or mental, or other situation or condition which, in the opinion of the 
Investigator, could represent an increased risk for the subject or impact the subject’s ability 
to comply with protocol requirements 
 

 
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4.1.2 Primary Safety Endpoint 
The primary safety endpoint is the proportion of women in the study who experience a serious 
adverse event or serious device-related adverse event.  The analysis of this endpoint will be 
descriptive.  The number of women experiencing a serious adverse event or serious device-
related adverse event, the number evaluated, the percentage and the 95% exact confidence 
interval will be presented. In addition, these items will be provided for specific individual events.   
 
4.1.3 Sample Size 
Assuming the success rate of the Cerene device in the ITT population is 75%, then 242 subjects 
will provide at least 85% power to show Cerene is superior to an OPC of 66% with an overall 
Type I error rate < 2.5%. If 5% of patients drop-out, then the Cerene device must have a success 
rate among patients with complete 12-month follow-up of at least 79% in order to achieve a 
success rate in the ITT population of 75%.  If 10% of patients drop-out, then the Cerene device 
much achieve a success rate of approximately 84% among patients with complete 12-months 
follow-up in order to achieve a success rate in the ITT population of 75%.   
 
4.1.4 Study Populations 
All women for whom a treatment with the device is placed in the cavity and treatment is attempted 
comprise the intention-to- treat (ITT) population.  The primary effectiveness analysis will be done 
in the ITT population.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.1.5 Poolability 
Pooling of data across study sites involves two concepts.  The first is whether the data from the 
sites can be combined for analysis.  This concept is confirmed if the sites all used a common 
protocol, the sites were monitored for protocol compliance, and the data gathering instruments 
used at each site are identical. 
 
The second concept is whether the data from all sites can be sufficiently similar that it can be 
combined to estimate a common effect size for the endpoints.  The primary efficacy analysis will 

 
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pool data across all sites.  Secondary analyses will test the homogeneity of success proportions 
across sites.  This will be done by the Fisher-Freeman-Halton test.  If the P-value for this test of 
homogeneity has a P-value of 0.10 or less, the sites will be considered heterogeneous with 
respect to the primary endpoint analysis.  If that occurs, an estimate of the effect will be presented 
with Bayesian hierarchical modeling across sites.   
 
4.1.6 Adaptive Design Interim Analysis 
Interim analyses are planned when 100 and 175 patients have been treated and in the trial for 12 
months, i.e. when the first 100 and 175 patients have had the opportunity to complete follow-up 
for the 12-month primary endpoint. The trial may declare an early success at each interim 
analysis. Specifically, the trial may declare success early if there is at least a 97.9% probability 
that PE ≥ 0.66.  
 
Even if early success is declared, final trial success will be evaluated when all 242 patients have 
the opportunity to complete follow-up for the 12-month primary endpoint.  Final trial success is 
also defined as at least a 97.9% probability that PE > 0.66.  If an early success is declared, 
Channel Medsystems will approach FDA with an early request for market approval (i.e. PMA) of 
the Cerene device should there be at least a 97.9% probability that PE ≥ 0.66. Note that the final 
clinical report’s success rate will still be based on the evaluation when all 242 patients have the 
opportunity to complete follow-up for the 12-month primary endpoint.   
 
4.1.7  Patient Accountability and Missing Data 
Subjects that exit the study for any reason will be tabulated and the reason will be recorded.  Also 
an accountability analysis will be presented to show compliance with planned study visits.  The 
number and percentage of subjects with study visits will be presented based on the number that 
are eligible for each visit.  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 

 
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4.1.8 Statistical Method 
4.1.8.1 Character of Study Variables 
A routine assessment is done to assure that the data of the study complies with the assumptions 
of the tests to be used. 
4.1.8.2 Analysis of Baseline Characteristics of the Study Population 
A descriptive analysis of the subjects enrolled in the study will be presented.  For continuous 
variables the mean, standard deviation (SD), number evaluated, median, minimum, and 
maximum will be provided.  For categorical variables, the number with the characteristic, the 
number evaluated, the percentage, and the exact 95% confidence limits will be provided. 
4.1.8.3 Primary effectiveness analysis 
Yi12 be the 12 month PBLAC score for subject i.  Let Ii12 be the success indicator for the ith patient 
at 12 month.  Ii12 will be 1 where Yi12 is less than or equal to 75 and will be 0 where Yi12 is greater 
than 75.  Let π = Pr(Ii12 = 1) be the probability of success at 12 months.  We model the log odds 
of success,  
 = log(π/1-π) 
as having a normal distribution.  The prior distributions for the log-odds of success is  
 ~ N(0, 22), 
 
When converted from the log-odds scale back to the original probability scale, the resulting prior 
distribution for the log odds of success has a median of 50% and a 95% probability that the 
success rate is between 2% and 98%.  At each interim and at the final analysis we calculate the 
posterior probability that π > 66%. 
4.1.8.4 Longitudinal Modeling  
Patients will be assessed at 3, 6, and 12 months following enrollment.  We use a longitudinal 
model of the primary endpoint to allow these earlier observations to predict the final 12-month 
status.  At each interim analysis, some patients will have completed follow-up and we will have 
observed their 12-months endpoint.  These patients may also have earlier measures of the 
primary endpoint, such as at 3 and 6 months.  There will be patients with earlier observations of 
the primary endpoint who have not yet reached 12 months of follow-up.  We utilize the information 
from patients with incomplete follow-up to the extent that these earlier observations are correlated 
with the final 12-month value.  A Bayesian model is built to learn how the early endpoints are 
correlated with the final 12-month endpoint and patients with complete follow-up information this 
model.   
 
A linear regression model is created to model the association between the baseline, 3-, and 6-
month values with the 12-month value. Therefore, there are three instances of the model.  Each 
model instance is identical. 
 
 

 
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4.1.8.5 Operating Characteristics 
In order to determine the performance of this trial design, we simulated it 5000 times across 
various assumptions for the PBLAC over time. Under the null hypothesis, that response rate is 
the same as the OPC, 66%, this trial will declare success with 2.5% probability.  This is the 
simulated one-sided Type I error rate in this scenario.  Under an alternative hypothesis, that the 
response rate is 75%, this trial will declare early success with approximately 30% probability.  The 
total probability of trial success in this scenario is 87%.  This is the power of the trial in this 
scenario.  There is less than a 1% probability that a trial that qualifies an early success would not 
still be successful at the final analysis with complete data. 
4.1.8.6 Primary safety analysis 
The primary safety analysis will be a descriptive presentation of the proportion of subjects with 
any serious adverse event and/or serious device-related adverse event.  The number with an 
event, the number evaluated, the percent, and the exact 95% confidence interval will be provided.  
The total number of events will also be provided. A secondary analysis will be done for all adverse 
events and the same information will be provided. 
4.1.8.7 Additional Analyses (if any) 
1. 
Amenorrhea rates will be recorded and presented descriptively at Month 12. 
2. 
Subject-reported procedure pain experience will be recorded and presented descriptively. 
3. 
Evaluation of dysmenorrhea at Month12 
4. 
Quality of Life (QOL) outcomes at six months and twelve months post-procedure 
compared to baseline (measured using MIQ and PMSIS) will be presented descriptively. 
5. 
Evaluation of uterine access and healing at twelve months post-procedure will be 
assessed and reported descriptively. 
6. 
Additional medical or surgical interventions to address excessive bleeding will be reported 
descriptively. 
4.1.8.8 Detailed Statistical Analysis Plan 
Prior to database lock for the interim analysis, a detailed statistical analysis plan will be drafted 
and approved. 
 
5 
Study Methods 
5.1 
Institutional Review Board / Ethics Committee Approval 
The Sponsor will obtain national regulatory authority approvals prior to initiating the study at a 
clinical site.  The study will be conducted in accordance with the applicable local law(s) and 
regulations in the country in which it is conducted, all requirements set forth in the clinical protocol, 
Good Clinical Practices (GCP), the provisions of the Declaration of Helsinki (World Medical 
Association Declaration of Helsinki, 2000), and the Sponsor’s Clinical Department Standard 
Operating Procedures . 
 
The investigator will obtain prospective approval of the study protocol, protocol 
amendments/changes, Informed Consent Form, and other relevant documents (e.g. 

 
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advertisements) from the IRB/EC prior to study start at his or her site.  All correspondence with 
the IRB/EC should be retained in the site study file.   
 
5.2 
Informed Consent 
The complete study and its required visits and assessments will be carefully discussed with the 
study subjects using an IRB/EC approved informed consent from (ICF).   
 
The Investigator or designee will explain all relevant aspects of the study to each subject to 
facilitate her understanding of the information.  Topics to be discussed include and are not limited 
to:  study purpose, screening procedures, study procedures, follow-up visits, risks and 
discomforts, alternative treatments.  Each subject will be provided ample time and opportunity to 
ask questions, have questions answered, and, without coercion or undue influence, to consider 
whether to voluntarily participate. The subject will be informed about the right to withdraw from 
the study at any time without prejudice.  The subject will sign the ICF before any study specific 
examinations and/or procedures are performed to confirm subject eligibility.  The clinical site will 
retain the original signed ICF in the subject’s study file or medical record or per institutional 
requirement and provide the subject with a copy of the signed and dated ICF.   
 
The ICF to be used should be the IRB/EC approved version.  The ICF and any other written 
information provided to a subject will be revised whenever important new information becomes 
available that may be relevant to the subject’s consent, or there is an amendment to the protocol 
that necessitates a change to the content of the subject information and / or the written ICF.  Any 
revision to the ICF must be approved by the IRB/EC prior to use.  The Investigator will inform the 
subject of changes to the ICF, ask the subject to confirm her agreement to continue participate in 
the study by signing the revised ICF, and provide the subject with the revised copy.  The signed 
ICF for each subject will be available for inspection by the Sponsor (or designee), FDA, IRB/EC, 
or other regulatory agency at the clinical site. 
 
5.3 
Study Identification Number 
The subject will be assigned a unique study identification number (Study ID number) after signing 
the ICF.  The subject number will be sequential in the order in which a subject signs the ICF.  The 
study ID number, used to identify the subject throughout the study, will include a unique country 
number, site number, and subject number.   
 
5.4 
Investigational Device Training 
Investigators will be fully trained in the proper use and operation of the Cerene Device before the 
initiation of subject treatments.  
 
 
 
 
 

 
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5.5 
Safety Data Review 
Channel Medsystems, Inc., or its designee, will review the clinical study progress and safety data 
periodically and as needed with a Medical Advisory Board (MAB) and/or a Clinical Events 
Committee (CEC).  
 
 
 
All records of event review will be documented and maintained 
in the sponsor’s master study file.   
 
5.6 
Subject Exit  
Subjects are considered to have completed the study when follow-up through month 36 post 
treatment has been achieved.  Subject participation is voluntary.  The subject may discontinue 
her participation in the study without prejudice or may be withdrawn from the study.  If a subject 
exits the study, a subject exit CRF will be completed with the reason for exit. 
 
 
 
 
 
 
  
 
  
 
5.7 
Premature Study Termination 
The Sponsor has the right to close or suspend this study at any time due to a change in the risk-
benefit ratio, interim analysis, study conduct, or other.  The Sponsor may terminate an Investigator 
and site from participation if there is evidence of an Investigator’s failure to maintain adequate 
clinical standards or evidence of continued serious protocol deviations.   
 
If the study or a specific site is closed prematurely, regulatory bodies, IRBs/ECs, and study 
subjects will be promptly notified.  Site investigators will discuss with subjects any standard of 
care for future medical follow-up.  The Sponsor will provide the site with details regarding archiving 
of study data and retention, return, or destruction of other study materials.   
 
 

 
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6 
Schedule of Study Procedures and Assessments 
 

 
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To qualify for treatment, the subject must record her menstrual blood loss using a PBLAC diary 
to confirm a PBLAC menstrual blood loss score of ≥ 150, within 3 months of informed consent, 
as follows: 
 
For two baseline cycles; OR 
 
For one baseline cycle if the subject has at least 3 prior months documented failed medical 
therapy, or a contraindication to medical therapy, or cannot tolerate medical therapy, and/or 
was offered and declined medical therapy. 
 
Sites will collect and review subject screening PBLAC diaries.  The screening PBLAC diary(s) will 
be scored to confirm the subject meets the PBLAC inclusion criteria.  If the investigator determines 
that the screening PBLAC diary was not recorded correctly, the subject may be asked to complete 
another diary for an additional menstrual cycle.  
 
Subjects treated with the Cerene device will be required to maintain a monthly PBLAC diary to 
track their blood loss after ablation treatment.  
 
 
 
   
 
 
 
 
 
 
   
 
 

 
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If the subject becomes amenorrheic following ablation treatment, the investigator will determine 
whether a urine and/or blood test for pregnancy is indicated, based upon subject symptoms. 
 
6.3 
Endometrial Thinning  
Endometrial thinning prior to ablation is recommended and can be achieved through medication 
or timing of the menstrual cycle to the early proliferative phase, per Investigator discretion. 
 
6.4 
Cerene Ablation Treatment 
6.4.1 Subject Preparation for Treatment 
 
Urine for pregnancy 
 
Confirm subject eligibility 
 
Uterine sound measurements 
 
Endometrial thickness measurement: 
 
 
Administer pre-procedure medications for anesthesia and/or analgesia 
 
6.4.2 Ablation Treatment 
NOTE:  Introduction of air and/or bubbles via saline hysteroscopy immediately prior to the ablation 
could interfere with the subsequent ablation.  Use of CO2 hysteroscopy is not indicated 
immediately prior to ablation.  Hysteroscopy, of any kind, immediately post ablation treatment is 
not indicated. 
 
Prepare subject for ablation procedure per standard practice 
 
Administer local analgesics, paracervical block, and anesthesia per investigator 
discretion 
 
Record all analgesia/anesthetics administered 
 
Initiate the ablation treatment with the Cerene Device per the Instructions for Use and 
physician training materials 
 
Assess and record subject’s pain intensity (0-10): 
1. After subject preparation and cervical dilation, but before device insertion  
2. After device insertion (before liner deployment)  
3. After liner deployment (before ablation)  
4. After 1 minute of ablation  
5. At end of ablation 
6. Post ablation: one additional pain measurement between >15 and 30 
minutes, inclusive. 
 
Ultrasound monitoring during device placement and ablation may be used, but is not 
mandatory 

 
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 
Dispose of Nitrous oxide per standard hospital procedure and/or according to 
Instructions for Use and physician training materials 
 
6.5 
Post-Treatment through Discharge 
 
Allow the subject to recover following treatment and monitor her per standard practice  
 
Record medication administered post-procedure 
 
Record adverse events 
 
Assess and record subject’s pain intensity at discharge/dischargeability 
 
Record the subject’s time and date of discharge 
 
 
 
 
 
 
 
 
  
 
Record time and date the subject is eligible for discharge 
 
 
 
 
 
 
6.6 
Day 1 Post treatment (+3 days)  
 
Contact subject next day after Cerene Device treatment procedure to assess status 
(telephone or office visit) 
 
Record subject’s adverse events 
 
Assess subject’s pain intensity (0-10)  
 
6.7 
Week 2 Post treatment (+ 2 weeks) 
 
Perform pelvic exam  
 
Query subject on return to activities of daily living 
 
Record Adverse Events  
 
Review PBLAC diary recording and instructions.  Remind subject to submit monthly 
PBLAC diary. 
 
Query subject regarding the use of additional medications or surgical procedures to 
manage heavy menstrual bleeding 

 
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6.8 
Month 3 Post treatment (± 4 weeks) 
 
Perform pelvic exam, if needed 
 
Administer MIQ and PMSIS questionnaires 
 
Collect and review PBLAC 
 
Query subject regarding the use of additional medications or surgical procedures to 
manage heavy menstrual bleeding 
 
Record Adverse Events since last follow-up 
 
6.9 
Month 6 Post treatment (± 4 weeks) 
 
Perform pelvic exam, if needed 
 
Administer MIQ and PMSIS questionnaires 
 
Collect and Review PBLAC 
 
Query subject regarding the use of additional medications or surgical procedures as 
intervention to manage heavy menstrual bleeding 
 
Record Adverse Events since last follow-up 
 
6.10 Month 12 Post treatment (± 4 weeks) 
 
Perform pelvic exam  
 
Collect FSH when age is > 40 years 
 
Administer MIQ and PMSIS questionnaires 
 
Assess uterine cavity access and healing via hysteroscopy 
 
Collect and Review PBLAC 
 
Query subject regarding the use of additional medications or surgical procedures as 
intervention to manage heavy menstrual bleeding 
 
Record Subject satisfaction and recommendation 
 
Record Adverse Events since last follow-up 
 
 
 
 
  
 
6.11 Month 24 Post Treatment (± 4 weeks) 
Collect the information listed below during the subject’s office or telephone contact visit. 
 
Query the subject regarding: 

 
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1. Any medication that she is taking or any surgical procedure or other treatment 
that she has undergone for uterine bleeding 
2. Gynecologic adverse events 
3. Type of contraception, compliance with contraception, and if she is pregnant or 
had a pregnancy 
4. Menstrual status 
5. Satisfaction with the results of the Cerene treatment and willingness to 
recommend the procedure to a friend or relative 
 
Administer the MIQ and PMSIS questionnaires during the contact 
 
6.12 Month 36 Post Treatment (± 4 weeks) / Subject Exit 
Collect the information listed below during the subject’s office or telephone contact visit. 
 
Query the subject regarding: 
1. Any medication that she is taking or any surgical procedure or other treatment 
that she has undergone for uterine bleeding 
2. Gynecologic adverse events 
3. Type of contraception, compliance with contraception, and if she is pregnant or 
had a pregnancy 
4. Menstrual status 
5. Satisfaction with the results of the Cerene treatment and willingness to 
recommend the procedure to a friend or relative 
 
Administer the MIQ and PMSIS questionnaires during the contact 
 
Exit subject at this visit per protocol 
 
7 
Adverse Event Reports 
An adverse event is any sign, symptom, illness, clinically significant abnormal laboratory value, 
or other adverse medical event that appears or worsens in a subject during a clinical study, 
regardless of whether or not it is considered related to the procedure / investigational device.  
 
Anticipated signs and symptoms (e.g. nausea, cramping) which occur in the recovery room will 
not be considered adverse events unless they occur with greater severity or intensity than 
anticipated.   
 
It is the responsibility of the investigator to report all adverse events as required by this protocol.  
Adverse event information will be collected throughout the study at each subject contact as 
defined in the table below.  Adverse events will be recorded on the Adverse Event CRF by the 
investigator or study coordinator and include start and stop date, anticipated or unanticipated, 

 
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A serious adverse event must be followed until it has subsided or, in case of permanent 
impairment or residual effects, until the event stabilizes, and the overall clinical outcome has been 
ascertained.  
 
Severity of Adverse Events: The definitions below will be used to rate the severity of adverse 
events for this study.  
 
Mild: Awareness of signs or symptoms, but easily tolerated and transient; causing no 
loss of time from normal activities; symptoms would not require medication or a 
medical treatment; signs and symptoms are transient. 
 
Moderate: Marked symptoms and discomfort severe enough to cause moderate 
interference with the subject’s usual activities.  Symptomatic treatment is possible. 
 
Severe: Incapacitating with inability to do work or usual activities; signs and symptoms 
may be of systemic nature or require medical intervention and/or treatment. 
Hospitalization may be required or prolonged. 
 
Serious Adverse Events (SAE):  An Adverse event is categorized as an SAE if it meets any of 
the criteria listed below.  SAE categorization is independent of the severity rating applied above. 
 
Death 
 
Life-threatening: the subject was at substantial risk of dying at the time of the adverse 
event, or if use or continued use of the device or other medical product might have 
result in the death of the subject 
 
Hospitalization (initial or prolonged) due to an adverse event 
Emergency room visits that do not result in admission to the hospital will be evaluated 
for one of the other serious outcomes (e.g., life-threatening; required intervention to 
prevent permanent impairment or damage; other serious medically important event). 
A hospitalization or prolongation of hospitalization will not be regarded as an SAE if at 
least one of the following exceptions is met: 
o 
The admission results in a hospital stay of less than 12 hours 
o 
The admission is pre-planned (such as elective or scheduled surgery arranged 
prior to the start of the study) 
o 
The admission is not associated with an AE (such as hospitalization for purposes 
of respite care) 
 
Disability or permanent damage 
o 
Disability means a substantial disruption of a person’s ability to conduct normal life’s 
functions 
 
Requires medical or surgical intervention to prevent permanent impairment of a body 
function or permanent damage to a body structure 
 
Congenital anomaly / birth defect caused by exposure to a medical product prior to 
conception or during pregnancy 

 
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 
Any medically important serious adverse event as judged by the investigator 
This includes an adverse event that does not fit the other outcomes, but it may 
jeopardize the subject and may require medical or surgical intervention (treatment) to 
prevent one of the other outcomes. Examples include allergic bronchospasm requiring 
treatment in an emergency room, serious blood dyscrasias (blood disorders) or 
seizures/convulsions that do not result in hospitalization.  The development of drug 
dependence or drug abuse would also be examples of important medical events. 
 
Serious Deterioration in the State of Health, per Health Canada SOR/98-282: 
 
Serious Deterioration in the State of Health, as defined in the Health Canada 
Regulations, involves: life-threatening disease, disorder or abnormal physical state,  
 
The permanent impairment of a body function or permanent damage to a body 
structure, or  
 
A condition that necessitates an unexpected medical or surgical intervention to 
prevent such a disease, disorder or abnormal physical state or permanent 
impairment or damage. 
 
Unanticipated Adverse Device Effect (UADE):  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 a supplementary plan or application, or investigator’s 
brochure), or any other unanticipated serious problem associated with a device that relates to the 
rights, safety, or welfare of subjects. 
 
Near incident:  Any malfunction or deterioration in the characteristics and/or performance of the 
device which might have led to death or serious deterioration in health; incident occurred and is 
such that if it occurred again, it might lead to death or serious deterioration in health. 
 
Adverse Event Relationship:  The relationship of an Adverse Event to a pre-existing condition, 
underlying disease, screening procedure, ablation procedure or treatment, or the device will be 
attributed as not related or related. 
 
Adverse Event Status (outcome):  The outcome of an adverse event should be assessed at 
every subject contact to determine if it has resolved or stabilized, or is ongoing.  It can be updated 
if new information is received.  The status should be recorded as follows: 
 
Resolved: the AE has stopped and the stop date should be recorded.  
NOTE: The severity of an AE may change.  If the severity changes, the AE with 
the existing severity should be recorded as resolved and the stop date when the 
severity changed should be entered.  A new AE with the updated severity 
should be recorded with a start date that the severity changed.   
 
Resolved with residual side effects:  this outcome would be recorded if the AE has 
stabilized but a pathological or residual condition continues. Therefore, the AE 

 
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symptom(s) has not completely resolved and a new baseline for the subject/ 
patient is established since full recovery is not expected (the AE is expected to 
continue for an undetermined amount of time).  A stop date for the AE should be 
recorded as the approximate date of AE stabilization. 
 
Not resolved:  this outcome would be recorded at subject exit if the adverse event 
has not stopped or stabilized.  A stop date for the AE should NOT be recorded. 
 
Fatal: this outcome would be recorded if the subject expired.  The stop date for the 
AE is recorded as the date of death. 
 
Other: this outcome would be recorded if any of the outcomes listed above do not 
apply.  The reason for other should be specified.  A stop date for the AE may or 
may not be recorded. 
 
8 
Risks and Benefits 
8.1 
Potential Risks to the Subject 
Participation in this clinical study may expose the subject to potential risks associated with the 
device or the procedure.  Safety events will be collected and reviewed throughout the study.  
Investigators will be notified of any additional risks identified during the study that could affect the 
health, safety, or welfare of the study subjects. 
 
Risks associated with the use of the Cerene Device are anticipated to be similar to risks 
associated with other endometrial cryoablation products.  The list of potential risks, provided 
below, is based on a review of scientific literature, animal studies, product risk and clinical risk 
analyses performed by the Sponsor.   
 
Abdominal bloating 
 
Abdominal pain 
 
Additional intervention for bleeding 
 
Anesthesia-related, adverse reaction or over-medication 
 
Cervical stenosis 
 
Cervical tear/injury 
 
Damage to adjacent organs (e.g. bowel burn or bladder injury) (Note:  a severe bowel 
injury could potentially lead to death)  
 
Dysmenorrhea 
 
Dyspareunia 
 
Embolism 
 
Endometritis 
 
Fever 
 
Hematometra 
 
Infection, sepsis, or death due to sepsis 
 
Nausea 

 
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 
Nitrous oxide impairment (dizziness) 
 
Pelvic cramping 
 
Pelvic or abdominal injury resulting from excessive uterine pressures 
 
Possible missed diagnosis of uterine cavity pathology post-endometrial ablation 
 
Post-ablation tubal sterilization syndrome 
 
Pregnancy (Note: Pregnancy following ablation may be life threatening to both mother 
and fetus) 
 
Urinary tract infections 
 
Uterine perforation 
 
Uterine synechiae (Asherman’s syndrome) 
 
Vaginal bleeding 
 
Vaginal discharge 
 
Vomiting 
 
Some or all of these risks may require a need for reoperation or subsequent treatment 
and/or may lead to permanent disability or death. 
 
Note: Vaginal discharge usually happens during the first few days following treatment and may 
last as long as six weeks.  It is generally described as bloody during the first few days, a 
mixture of blood and fluid for another week, then followed by a watery discharge that can 
be substantial at times.  This is an anticipated symptom of the cryotherapy treatment and 
is not considered an adverse event unless the vaginal discharge suggests infection. 
 
There is also the possibility of an unanticipated reaction to the study device and/or medications 
used during the procedure that could require emergency intervention.  Subjects with known 
sensitivity to drugs that may be used during the procedure are excluded from study participation.  
Should a subject experience a significant side effect for which there is concern, she will be 
managed per investigator standard of care and institutional requirements. 
 
If sedation is used, potential risks from the agents and/or gases used include postoperative pain, 
nausea and vomiting, dizziness, drowsiness, shivering, liver toxicity, and/or cardiovascular 
events.  Trained professionals with extensive experience and expertise who routinely administer 
anesthesia to subjects will be responsible for the induction and associated monitoring required 
for this type of procedure.  Study subjects will be monitored throughout treatment, recovery, and 
discharge per investigator and institution requirements.  In addition, the risks of blood draws 
include temporary pain and discomfort from the needle stick, and/or tenderness, redness or 
bruising at the site, bleeding, fainting and lightheadedness.  
 
This list of risks may not be complete and it is possible that unforeseen risks could occur.  There 
is also the risk that the procedure may not be effective or the subject may not be able to be treated 
because of obstructions within the cavity, an unusual cavity shape, or inadequate uterine 
dimensions that are determined at completion of screening on the day of study treatment. 
 

 
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8.2 
Insurance Coverage 
Channel Medsystems, Inc. maintains clinical trial insurance coverage for this study in accordance 
with the laws and regulations of the country in which the study it is being performed.  
Documentation will be provided upon request. 
 
8.3 
Potential Benefits to the Subject 
It is possible that Subject will not receive any benefits from treatment with the Cerene Device.  
Potential benefits of treatment that may be realized by study participants include overall fewer 
symptoms related to heavy menstrual bleeding and improved quality of life. In addition, subjects 
participating in the study is the ability to learn more about their heavy menstrual bleeding, based 
on the assessments that will be performed throughout the course of the study.  In addition, the 
subjects will receive education about the monitoring of their disease, as will be required for study 
participation. 
 
9 
Study Monitoring 
In accordance with applicable regulations, GCP, and Sponsor procedures, when subject 
enrollment is initiated, study monitors will meet with clinical site staff to review the protocol, subject 
eligibility criteria, study requirements, data collection and reporting requirements, and the 
investigator’s responsibilities to satisfy regulatory, ethical, and Sponsor’s requirements.  The 
study monitor will identify the types and location of source documentation in use at the site.  
 
The study monitor will monitor study data to verify that the subject’s rights and well-being are 
protected, the study investigator is conducting the study in compliance with the protocol and the 
investigator’s agreement, and to ensure reported data are authentic, accurate and complete.  
Remote and on-site data monitoring will be utilized.  It is the Investigator’s responsibility to ensure 
the accuracy, completeness, and timeliness of the data reported in the subject’s CRF.   
 
The Investigator will allow direct access to subject files and source documents for the purpose of 
verifying CRF entries and assist with the study monitor’s activities as required.  Clinical site staff 
will provide adequate time, office accommodations, and resources (including copy machine, 
phone, and/or internet access) to the study monitor for monitoring visits.  Source documentation 
supporting the CRF data should indicate the subject’s participation in the study and should 
document the dates and details of study procedures, AEs, and subject status.  Source documents 
must be signed and dated by the investigator or designee for each visit.   
 
A third-party monitor has been appointed as the data management CRO for this study. 
Study Monitor: 
 
 
 
 
 
 
 

 
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9.1 
Responsibilities of the Sponsor 
Sponsor responsibilities include but are not limited to:  
 
Conducting this clinical study in compliance with all applicable regulatory requirements 
and guidelines, specifically in accordance with FDA regulations as described in 21 
CFR 50 and 56 and 812, ISO 14155:2011(E) Clinical investigation of medical devices 
for human subjects – Good clinical practice, IRB/EC requirements, and the Informed 
Consent provisions of the Declaration of Helsinki. 
 
Ensuring study oversight. 
 
Monitoring study data to verify that the subject’s rights and well-being are protected.  
 
Informing the clinical investigator of any new information about the study that may 
affect the health, safety or welfare of the subjects, or which may influence her decision 
to continue participating in the study. 
 
Providing the clinical investigator with the study protocol and the CRFs on which to 
document the study evaluation variables for each subject. 
 
Selecting qualified investigators to conduct this clinical study. Each Investigator will 
sign an Investigator Agreement prior to the study start.  Financial Disclosure 
Statements will be completed, as required. 
 
Maintaining copies of correspondence, records of shipment and disposition of devices, 
adverse device effects, records related to the signed investigator agreements, and 
other records related to the clinical study. 
 
9.2 
Responsibilities of the Investigator 
Each clinical investigator that will perform treatments with the investigational device in this clinical 
study must be licensed a physician in his/her country of employment.  The investigator will affirm 
by his/her signature on the Investigator's Agreement that he/she will fulfill his/her responsibilities 
to this clinical study. 
Investigator responsibilities include but are not limited to:  
 
Protecting the rights, safety, and welfare of subjects under his/her care 
 
Ensuring that all subjects meet eligibility criteria prior to treatment 
 
Obtaining initial and ongoing IRB/EC Approval of the protocol 
 
Obtaining subject informed consent using an IRB/EC approved informed consent form 
 
Performing subject evaluations and reporting data as specified in the protocol 
 
Documenting and reporting protocol deviations 
 
Retaining original records for the timeframe required by local regulation or longer per 
Sponsor instruction 
 
Ensuring investigational devices are dispensed only to study subjects and under the 
direct supervision of the investigator or co-investigators 
 
Maintaining records of investigational device disposition 

 
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10 Record Keeping and Report Requirements 
10.1 Subject Confidentiality 
Subject confidentiality shall be maintained at all times throughout the conduct of the study, and 
all subject data shall be maintained secure against unauthorized access.  Whenever possible, 
subject names will not be provided to the Sponsor.  Only the study ID number will be recorded on 
the CRF.  During the informed consent process, the subject will be informed that representatives 
of the Sponsor, IRB/EC, or regulatory authorities may inspect, review, and photocopying of the 
subject records and that all personal information will be maintained in strict confidence and in 
accordance with local data protection requirements and/or laws.  In the event a subject’s data are 
used for educational, presentation, and/or publication purposes, subject identity will be masked 
to protect the subject’s confidentiality. 
 
10.2 Protocol Deviations 
The investigator must adhere to all specifications defined in this protocol.  The study investigator 
should not deviate from the protocol, unless the study plan poses unacceptable risks to the health 
or welfare of the involved individual subject.  The investigator shall notify Channel Medsystems 
Inc. and the reviewing ethics committee of any deviation from the protocol intended to protect the 
life or physical wellbeing of a subject in an emergency.  Such notice shall be given as soon as 
possible, but in no event later than five working days after the emergency occurred.  Except in 
such an emergency, prior approval of Channel Medsystems Inc. is required for any deviation from 
the protocol.  Approval from the IRB/EC also is required if these changes or deviations are 
expected to affect the rights, safety or welfare of human subjects. 
 
10.3 Investigator Reports 
Investigators are required to prepare and submit the following complete, accurate and timely 
reports on this investigation (See Table below) 
 
 

 
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