Clinical trial NCT04248153
Conditions: Ovarian Cancer
Sponsor: Bracco Diagnostics, Inc
Start date: 2019-10-14; Completion date: 2021-07-31
Enrollment: 3 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an exploratory, single center, open label, prospective study of BR55 to determine the optimal phase of the menstrual cycle for performing BR55 contrast-enhanced ultrasonography (CEUS) of the target ovary in premenopausal women scheduled to undergo preventative surgery because of high familial/hereditary or genetic risk for ovarian cancer.

Detailed description:

Arms: arm 1: BR55 will be performed in the early follicular phase first and in the late follicular phase thereafter. arm 2: BR55 will be performed in the late follicular phase first and in the early follicular phase thereafter.
Interventions: intervention 1: BR55
Intervention descriptions: intervention 1: BR55 will be administered at doses of 0.03 mL/kg or 0.05 mL/kg

Protocol documents:
Prot_SAP_000.pdf: 
Document ID: BDI-PTR-AC2838.17-BR55109S-B079212-2.0 
Confidential 
Page 1 
 
 
Angiogenesis Agents- KDR Microbubbles 
Protocol WWM&RA 
Synopsis 
 
CONFIDENTIAL 
An Exploratory Study to Determine the Optimal Timing of BR55 
Contrast Enhanced Ultrasound (CEUS) of the Ovaries in  
Pre-menopausal Women 
 
BR55 
Protocol No.: 
Final Protocol Date: 
IND No.: 
Fully Amended Synopsis:  
BR55-109  
27 February 2017 
114098 
(including Amendment No.: 01) 
Final Version 
05 March 2019 
 
SPONSOR MEDICAL EXPERT:  
Maria Luigia Storto, MD  
 
 
 
 
 
Sponsor: 
Bracco Diagnostics Inc. 
 
 
The information contained in this document is the property of Bracco Group.  It contains strictly confidential 
information and no part of this document will be published or disclosed without Bracco Group prior written 
permission except that this document may be disclosed to appropriate Institutional Review Board/Ethics 
Committee/Regulatory Authorities/Competent Authorities as long as they are required to keep it confidential. 


Fully Amended Synopsis No. 1 
BR55-109  
Final Version  
05 March 2019 
Optimal Timing of BR55 CEUS of the 
Ovaries 
BR55
 
Document ID: BDI-PTR-AC2838.17-BR55109S-B079212-2.0 
Confidential 
Page 2 
 
Protocol Title 
An Exploratory Study to Determine the Optimal Timing of BR55 Contrast Enhanced Ultrasound 
(CEUS) of the Ovaries in Pre-menopausal Women. 
Protocol No. 
This study is being conducted under protocol number: BR55-109.   
IND number: 114098 
Objectives 
The objectives of this exploratory study are: 
• to determine the optimal phase of the menstrual cycle for performing BR55 CEUS of the 
target ovary in premenopausal women at high risk for ovarian cancer; 
• to expand the safety profile of the BR55 in subjects with potential ovarian cancer. 
Additional exploratory objectives are:  
• to correlate the signal intensity (SI) within the target ovary as seen at BR55 CEUS with 
histopathology findings; 
• to assess the correlation between SI within the target ovary as seen at BR55 CEUS and 
Vascular Endothelial Growth Factor Type 2 (VEGFR2) expression as determined by 
immunohistochemistry (IHC); 
• to assess the correlation between SI within the target ovary as seen at BR55 CEUS and 
microvessel density (MVD). 
Investigational Plan  
This is an exploratory, single center, open label, prospective study of BR55 to determine the 
optimal phase of the menstrual cycle for performing BR55 CEUS of the target ovary in 
premenopausal women scheduled to undergo preventative surgery because of high 
familial/hereditary or genetic risk for ovarian cancer. This study will be conducted at Stanford 
University Medical Center. 
Training Cases 
The site will enroll up to 3 subjects as “training cases” to determine the optimal imaging 
technique with BR55 and a 2D intracavitary probe for this study population. 
Subjects enrolled for training purposes will undergo all safety evaluations but not the efficacy 
assessments and will not be required to undergo oophorectomy. These subjects will receive a 
single CEUS examination with administration of BR55 at a dose of 0.03 mL/kg. Timing of the 
CEUS examination with respect to follicular phase of the menstrual cycle will not be considered. 
 


Fully Amended Synopsis No. 1 
BR55-109  
Final Version  
05 March 2019 
Optimal Timing of BR55 CEUS of the 
Ovaries 
BR55
 
Document ID: BDI-PTR-AC2838.17-BR55109S-B079212-2.0 
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Efficacy Cases 
Subjects enrolled in the efficacy phase of the study will undergo two BR55 CEUS examinations: 
one examination during the early follicular phase (i.e. just after menstruation) and one 
examination during the late follicular phase (i.e. right before ovulation).  The timing of the late 
follicular phase will be determined on the basis of the subject’s clinical history with regard to the 
menstrual cycle and assessment of luteinizing hormone levels in the urine. SI within the target 
ovary will be quantitatively assessed for each of the two CEUS examinations with BR55 and 
compared for presence of significant differences. 
All subjects will undergo preventative salpingo-oophorectomy within five days of the second 
BR55 CEUS (oophorectomy is not required for training cases); histopathology and IHC results 
will be compared with BR55 findings seen on the second CEUS examination. 
Subjects will be randomized to the follicular phase for undergoing the first BR55 CEUS in the 
early or late follicular phase as follows: 
Group A: BR55 CEUS will be performed in the early follicular phase first and in the late 
follicular phase thereafter 
Group B: BR55 CEUS will be performed in the late follicular phase first and in the early phase 
thereafter 
BR55 dose will be evaluated in the study as follows:  
The first 10 subjects enrolled in the study will receive BR55 at a dose of 0.03 mL/kg. Assuming 
these first 10 subjects will show technically adequate images, subsequent subjects enrolled in the 
study will continue to receive 0.03 mL/kg dose of BR55; otherwise, subjects will be switched to 
a 0.05 mL/kg dose. 
Study Duration  
A subject’s participation will begin at the time of signing the informed consent. 
The BR55 CEUS exam will be completed within 60 minutes at maximum after BR55 
administration (including 30 minutes of CEUS examination). 
Safety monitoring will begin at the time of signing the Informed Consent Form and will continue 
through the follow-up evaluations at 24 hours after the first BR55 administration (first BR55 
CEUS exam).  Safety monitoring will continue from 24 h prior to the second BR55 
administration through the follow-up evaluations at 24 h post second BR55 administration 
(second BR55 CEUS exam), if applicable. 
Study Population  
Subjects with a high risk of ovarian cancer scheduled to undergo preventative salpingo-
oophorectomy within 5 days, but not before 24 hours, after the second BR55 CEUS examination 
will be prospectively enrolled in the study. It is planned to enroll about 50 female subjects 
meeting inclusion and exclusion criteria, in order to obtain 47 evaluable subjects with normal 
bilateral ovaries and no occult cancer. 


Fully Amended Synopsis No. 1 
BR55-109  
Final Version  
05 March 2019 
Optimal Timing of BR55 CEUS of the 
Ovaries 
BR55
 
Document ID: BDI-PTR-AC2838.17-BR55109S-B079212-2.0 
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Additionally, the site will enroll up to 3 subjects as “training cases” to determine the optimal 
imaging technique with BR55 and a 2D intracavitary probe for this study population. Subjects 
enrolled for training purposes will undergo all safety evaluations and will be part of the safety 
population but will be excluded from the efficacy analyses. Therefore, timing of the CEUS 
examination with respect to follicular phase of the menstrual cycle and oophorectomy are not 
requirements for subjects enrolled in the training phase of the study. 
 
Inclusion Criteria 
Enroll a subject in this study if the subject meets the following inclusion criteria: 
• Is a female subject of at least 18 years of age; 
• Is premenopausal; 
• Is scheduled to undergo preventative salpingo-oophorectomy for high risk of ovarian 
cancer not earlier than 24 hours and not later than 5 days following the second BR55 
CEUS examination (with the exception of subjects enrolled in the training phase of the 
study); 
• Provides written Informed Consent and is willing to comply with protocol requirements 
Exclusion Criteria 
Exclude a subject from this study if the subject does not fulfill the inclusion criteria, or if any of 
the following conditions are observed: 
• Is a pregnant or lactating female. Exclude the possibility of pregnancy: 
- by testing on site at the institution (serum Beta Human Chorionic Gonadotropin, 
βHCG) within 24 hours prior to the start of investigational product (IP) administration, 
- by surgical history (e.g., tubal ligation or hysterectomy), 
• Has undergone prior systemic therapy for ovarian cancer;  
• Has history of concurrent malignancy; 
• Has history of any clinically unstable cardiac condition including class III/IV congestive 
heart failure;  
• Has had any severe cardiac rhythm disorders within 7 days prior to enrolment; 
• Has severe pulmonary hypertension (pulmonary artery pressure >90mmHg) or 
uncontrolled systemic hypertension and/or respiratory distress syndrome;  
• Has open and/or non-healing wounds in the chest, abdomen and pelvis;  
• Has other systemic vascular abnormalities associated with neovascularization that in the 
opinion of the investigator could significantly affect the ability to evaluate the effects of 
BR55;  


Fully Amended Synopsis No. 1 
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• Is participating in a clinical trial or has participated in another trial with an investigational 
compound within the past 30 days prior to enrolment; 
• Has previously been enrolled in and completed this study; 
• Has any known allergy to one or more of the ingredients of the Investigational Product or  
to any other contrast media; 
• Is determined by the Investigator that the subject is clinically unsuitable for the study; 
• Has had major surgery, including laparoscopic surgery, within 3 months prior to 
enrolment; 
• Has history of surgery to the ovaries or pelvic inflammatory disease. 
Discontinuation Criteria  
 
Clearly document the reason for the subject’s discontinuation on the Case Report Form (CRF). 
Discontinued subjects are not replaced.  Discontinue a subject from the study if the subject: 
• Withdraws consent; 
• No longer meets the Inclusion Criteria; 
• Experiences any of the Exclusion Criteria; 
• Has an adverse event that, in the opinion of the Investigator, requires the subject’s 
discontinuation. 
Investigational Products 
 
 
 
 
 


Fully Amended Synopsis No. 1 
BR55-109  
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Optimal Timing of BR55 CEUS of the 
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Administration 
The calculated dose of BR55 will be administered by slow IV bolus injection through an 
angiocatheter (20 Gauge). Strict adherence to aseptic technique must be maintained and subjects 
will be observed throughout the procedure. 
Subjects enrolled in the training phase of the study will receive BR55 at a lowest dose of 0.03 
mL/kg. 
The first 10 subjects enrolled in the study will receive BR55 at a dose of 0.03 mL/kg. Assuming 
the first 10 subjects will show technically adequate images, subsequent subjects will receive the 
BR55 dose of 0.03 mL/kg; otherwise, subjects will be switched to a 0.05 mL/kg dose of BR55.  
In each subject, the administration of BR55 will be followed by a 10 mL 0.9% saline flush. 
Methodology 
The Study Schedule is presented in Table B. 
Participants will sign an Informed Consent Form (that can be obtained within 10 days of BR55 
administration) prior to the conduct of any study procedures. Baseline evaluations will be 
conducted on all Study participants and include the collection of a complete medical history, 
gynecological history (including disease related medical history), a physical examination, weight 
measurement, vital signs, electrocardiogram (ECG), and collection of laboratory samples, plus a 
serum βHCG pregnancy test for women of child-bearing age and who have not had a 
hysterectomy.  
The unenhanced ultrasound (UEUS) and BR55 CEUS examinations will be performed with the 
same equipment and documented by images acquired according to instructions in the dedicated 
imaging manual. 
To ensure optimal BR55 CEUS timing in the late follicular phase, i.e. just before ovulation, 
patient history with regard to the menstrual cycle will be assessed along with measurements of 
luteinizing hormone levels in the urine. This will not apply to subjects enrolled in the training 


Fully Amended Synopsis No. 1 
BR55-109  
Final Version  
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Optimal Timing of BR55 CEUS of the 
Ovaries 
BR55
 
Document ID: BDI-PTR-AC2838.17-BR55109S-B079212-2.0 
Confidential 
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who will receive a single CEUS with BR55, independently from the phase of the menstrual 
cycle.  
For each BR55 CEUS examination, safety will be assessed through monitoring for Adverse 
Events, continuous monitoring of pulse oximetry from 10 minutes pre-dose through 30 minutes 
post dose, as well as measuring of vital signs, ECGs and collection of laboratory samples at the 
time points described in the Table B. 


Fully Amended Synopsis No. 1 
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Table B: Study Schedule 
 
FIRST BR55  CEUS EXAMINATION 
Events 
PRE-DOSE  
(before BR55 inj.) 
 BR55 
inj. 
POST-DOSE  
(after BR55 inj.) 
POST-DOSE  
Follow-up 
Within 
10d 
Within 
24h 
Within 
 2h 
-10 min 
Immed.  
prior 
+30 min 
+1 hr 
+24 h 
Written Informed Consent a 
× 
 
 
 
 
 
 
 
 
Pregnancy test  b 
 
× 
 
 
 
 
 
 
 
Test for ovulation c 
 
× 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
× 
 
 
 
 
 
 
 
Concomitant medications d 
 
× 
⇒ 
⇒ 
⇒ 
⇒ 
⇒ 
⇒ 
× 
Adverse Events Monitoring e 
× 
⇒ 
⇒ 
⇒ 
⇒ 
⇒ 
⇒ 
⇒ 
× 
Medical History f 
 
× 
 
 
 
 
 
 
 
Physical Examination 
 
× 
 
 
 
 
 
 
× 
Laboratory Evaluations 
 
× 
 
 
 
 
 
 
× 
Weight assessment 
 
 
× 
 
 
 
 
 
 
Vital Signs g 
 
 
× 
 
 
 
× 
× 
× 
Electrocardiogram 
 
 
× 
 
 
 
× 
× 
× 
Pulse oximetry 
 
 
 
× 
⇒ 
⇒ 
× 
 
 
UEUS exam 
 
 
 
 
× 
 
 
 
 
BR55 Administration 
 
 
 
 
 
× 
 
 
 
BR55 CEUS h 
 
 
 
 
 
× 
× 
 
 
a Obtain prior to implementation of any study procedures, within 10 days prior to BR55 administration. 
b For childbearing potential subjects perform a serum βHCG pregnancy test.  
c To ensure optimal BR55 CEUS timing in the late follicular phase (i.e. just before ovulation) perform a luteinizing hormone urine test. To be performed only 
 in subjects who will undergo the first BR55 CEUS during the late follicular phase of the menstrual cycle(not to be performed for the training subjects). 
d Record all medications (prescription and over-the-counter) taken within 24 hours prior up to 24 hours after BR55 administration. 
e Start monitoring from the time of signing Informed Consent and continue through the follow-up evaluations at  24 hours after the first BR55 administration. 
 Only post-dose events will be tabulated as adverse events. 
f Includes Demographics, Gynecological Medical History, disease related Medical History and General Medical History. 
g Includes systolic and diastolic blood pressure and heart rate. 
h Imaging will be performed as per instructions in the imaging manual. 


Fully Amended Synopsis No. 1 
BR55-109  
Final Version  
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Optimal Timing of BR55 CEUS of the 
Ovaries 
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SECOND BR55  CEUS EXAMINATION (not applicable for training cases) 
Events 
PRE-DOSE  
(before BR55 inj.) 
 
BR55 
inj. 
POST-DOSE  
(after BR55 inj.) 
POST-DOSE  
Follow-up 
Within 
24h 
Within 
 2h 
-10 min 
Immed.  
prior 
+30 min 
+1 hr 
+24 h 
within 5 days 
Pregnancy test  a 
× 
 
 
 
 
 
 
 
 
Test for ovulation b 
× 
 
 
 
 
 
 
 
 
Concomitant medications c 
× 
⇒ 
⇒ 
⇒ 
⇒ 
⇒ 
⇒ 
× 
 
Adverse Events Monitoring d 
× 
⇒ 
⇒ 
⇒ 
⇒ 
⇒ 
⇒ 
× 
 
Physical Examination 
× 
 
 
 
 
 
 
× 
 
Laboratory Evaluations 
× 
 
 
 
 
 
 
× 
 
Weight assessment 
 
× 
 
 
 
 
 
 
 
Vital Signs e 
 
× 
 
 
 
× 
× 
× 
 
Electrocardiogram 
 
× 
 
 
 
× 
× 
× 
 
Pulse oximetry 
 
 
× 
⇒ 
⇒ 
× 
 
 
 
UEUS exam 
 
 
 
× 
 
 
 
 
 
BR55 Administration 
 
 
 
 
× 
 
 
 
 
BR55 CEUS f 
 
 
 
 
× 
× 
 
 
 
Salpingo-oophorectomy g 
 
 
 
 
 
 
 
 
× 
a For childbearing potential subjects perform a serum βHCG pregnancy test. 
b To ensure optimal BR55 CEUS timing in the late follicular phase (i.e. just before ovulation) perform a luteinizing hormone urine test. To be performed only in subjects who 
 will undergo the second BR55 CEUS examination during the late follicular phase of the menstrual cycle (not to be performed for the training subjects). 
c Record all medications (prescription and over-the-counter) taken within 24 hours prior up to 24 hours after BR55 administration. 
d Resume safety monitoring 24 hours before the second BR55 administration and continue through the follow-up evaluations at 24 hours after the second BR55 
 administration.  Only post-dose events will be tabulated as adverse events. 
e Includes systolic and diastolic blood pressure and heart rate. 
f Imaging will be performed as per instructions in the imaging manual. 
g Salpingo-oophorectomy to be performed from 24 h up to 5 days after the second BR55 CEUS exam (with the exception of subjects enrolled in the training phase of the 
study). 


Fully Amended Synopsis No. 1 
BR55-109  
Final Version  
05 March 2019 
Optimal Timing of BR55 CEUS of the 
Ovaries 
BR55
 
Document ID: BDI-PTR-AC2838.17-BR55109S-B079212-2.0 
Confidential 
Page 10 
Subject Evaluations 
Medical History and Demographics 
Obtain a complete medical history and gynecological history (including disease related medical 
history and scheduled date for salpingo-oophorectomy) after the subject has signed the Informed 
Consent and within 24 hours prior to investigational product administration. 
Test for Ovulation  
To ensure optimal BR55 CEUS timing in the late follicular phase, i.e. just before ovulation, 
patient history with regard to the menstrual cycle will be assessed along with measurements of 
luteinizing hormone levels in the urine (this test will not be performed in the subjects enrolled in 
the training phase).  
Pregnancy Test 
Exclude the possibility of subject’s pregnancy: 
• by testing (serum βHCG) within 24 hours prior to the start of investigational product 
administration; 
• by surgical history (e.g., tubal ligation or hysterectomy). 
Concomitant Medications 
For each BR55 administration, record all medications (prescription and over-the-counter) taken 
within 24 hours pre-dose and up to 24 hours post-dose in the Concomitant Medication section of 
the Case Report Form.  Any medication taken for treatment of an adverse event that occurred 
after the subject signed the informed consent form should be recorded. 
Safety Assessment 
Adverse Events 
Subjects will be monitored for any untoward medical occurrences from the time of signing of 
Informed Consent through 24 hours after the first administration of BR55 (first BR55 CEUS 
exam); monitoring will resume from 24 hours prior to the second BR55 injection and continue 
through the follow-up evaluation at 24 hours after the second administration of BR55 
administration (second BR55 CEUS exam), if applicable. Record all untoward medical events in 
the Adverse Event section of the CRF as specified in the protocol.  Only post-dose untoward 
medical occurrences will be tabulated as adverse events. 
All serious adverse events that occur during the study monitoring period are required to be 
collected regardless of the relationship to BR55 on the Serious Adverse Event Report (SAER) 
Form.   
In addition, the investigator should report any serious adverse events that occur after the 
monitoring period that he/she believes may be related to the BR55 on the SAER Form. 


Fully Amended Synopsis No. 1 
BR55-109  
Final Version  
05 March 2019 
Optimal Timing of BR55 CEUS of the 
Ovaries 
BR55
 
Document ID: BDI-PTR-AC2838.17-BR55109S-B079212-2.0 
Confidential 
Page 11 
Physical Examination 
For each BR55 administration, perform a physical examination within 24 hours pre-dose and at 
24 hours post-dose. 
Weight measurements will be collected within 2 hours prior to each BR55 administration for 
dose calculation. 
Vital Signs 
For each BR55 administration, collect the following vital signs within 2 hours pre-dose and 
approximately at 30 min, 1 hour and 24 hours post-dose:  
• Systolic blood pressure (mmHg)  
• Diastolic blood pressure (mmHg) 
• Heart rate (beats/minute) 
 
Pulse Oximetry 
Monitor pulse oximetry from approximately 10 minutes prior to BR55 administration and 
continue through 30 minutes after each BR55 administration. During the monitoring period, any 
worsening of blood oxygen saturation in pulse oximetry noted from pre-dose, including the 
timing in respect to BR55 administration, must be recorded on the CRF. 
Laboratory Evaluations 
For each BR55 administration, collect blood and urine samples within 24 hours pre-dose and at 
24 hours post-dose for evaluation of the analytes listed in the protocol.  
A local laboratory will be utilized for analyzing and reporting laboratory results. 
Electrocardiograms 
For each BR55 administration, electrocardiograms (ECG) will be recorded within 2 hours pre-
dose and at approximately 30 minutes, 1 hour, and 24 hours post-dose.  
A local ECG laboratory will be utilized for analyzing and reporting ECG evaluations. 
Imaging Procedures  
Ultrasound equipment 
The ultrasound examination will be performed in the Department of Radiology of Stanford 
University Hospital with a FDA-approved ultrasound equipment commercially available for 
clinical applications, with a CEUS dedicated platform and equipped with an endocavitary 2D 
probe for obstetrics and gynecology examinations.  
A detailed description of the unenhanced ultrasound (UEUS) and BR55 contrast-enhanced 
ultrasound (CEUS) acquisition protocols will be provided in a dedicated Imaging Manual. 


Fully Amended Synopsis No. 1 
BR55-109  
Final Version  
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Optimal Timing of BR55 CEUS of the 
Ovaries 
BR55
 
Document ID: BDI-PTR-AC2838.17-BR55109S-B079212-2.0 
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Imaging Procedure outline 
Unenhanced Ultrasound 
Each BR55 CEUS examination will be preceded by UEUS examination. 
UEUS will be performed to ensure a comprehensive survey of the pelvic structures and organs 
and to identify the ovary with the corpus luteum, or any focal abnormality (if present in the 
absence of a corpus luteum). If neither the corpus luteum nor a focal abnormality is seen, then 
one of the two ovaries will be chosen as the target ovary by the investigator. The ovary chosen 
during this first examination will then also be used as the target ovary for the subsequent CEUS 
examination with BR55.  
 
Contrast Enhanced Ultrasound 
CEUS will be performed after administration of BR55 and upon activation of the low 
Mechanical Index (<0.2) contrast study preset. The image persistence needs to be set to OFF in 
order to facilitate the post-processing of acquired images with dedicated quantification software. 
After BR55 administration, the contrast inflow within the target ovary will be observed for 
approximately 45 seconds using a low frame rate to minimize destruction of targeted bubbles. 
Subsequently, post-contrast images will be acquired using a 2D probe at predefined time 
intervals of 2 minutes, starting from 2 minutes after administration of BR55 and up to 30 minutes 
post BR55 administration, or until stationary enhancement is no longer visible, whichever occurs 
first.  
To determine the optimal imaging technique for this study population, up to 3 subjects will be 
enrolled as “training cases”. The technical aspects in the training phase of the study will focus on 
the CEUS examination using the wash-in phase on a predefined plane of the target ovary 
followed by slow sweep acquisitions over the entire ovary (starting from one pole to the other or 
one site of the ovary to the other) for at least 2 sec per plane. After the images are acquired on 
the training subjects, a consensus review will be performed to determine the optimal imaging 
technique to be used for the remainder of the study.  
The Imaging Manual will be modified accordingly to describe the nuances in imaging technique.  
DICOM images will be transferred to Bracco Imaging Core Laboratory. 
Efficacy Evaluations 
For CEUS exams, a quantitative assessment of BR55 enhancement will be performed at each 
acquisition time point by drawing a Region of Interest (ROI) within the following predefined 
areas in the target ovary, as applicable: 
• corpus luteum, or focal abnormality (if present)   
• area of focal enhancement (if present) 
• normal tissue.  


Fully Amended Synopsis No. 1 
BR55-109  
Final Version  
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Optimal Timing of BR55 CEUS of the 
Ovaries 
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Document ID: BDI-PTR-AC2838.17-BR55109S-B079212-2.0 
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If more than one area of focal enhancement will be identified, the largest one will be considered 
for measuring of the SI. 
Histopathology measurements and immunohistochemistry assessment will be described in a 
separate dedicated manual. 
Statistical Methods 
Any major statistical methods deviated from the original statistical plan in this protocol will 
either be justified and approved in a protocol amendment or described in the separate statistical 
analysis plan, and then reported in the clinical trial report. 
In general, summary statistics (mean, median, standard deviation, minimum, and maximum) will 
be provided for continuous variables, and the number and percentage of each category will be 
provided for categorical data.  
All the data will be presented in the subject data listings. 
Subject Disposition and Demographic and Baseline Characteristics 
Subject completion status will be tabulated with number and percentages of subjects dosed and 
completed according to the protocol guidelines, and the reasons for any premature 
discontinuation will be presented. 
Summary tables will be provided for demographic and baseline characteristics, including age, 
weight, height, gender, and race for each dose, as applicable. 
Analysis Population 
Safety analysis population will consist of all subjects who are dosed. 
Efficacy analysis population will include the data from all subjects who are dosed and have 
efficacy data available. Training subjects will not be included in the efficacy analysis. 
Extent of Exposure 
Descriptive statistics will be presented to summarise the volume of investigational medicinal 
product administered.  Dosing of the BR55 will be listed. 
Safety Analysis 
All patients receiving any dosage of investigational product will be included in the safety 
population on which safety analyses will be carried out. Summary tables, including change from 
pre-dose to post-dose where applicable, will be presented for the following safety endpoints: 
• Adverse Events 
• Clinical Laboratory Evaluations 
• Vital Signs 


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BR55-109  
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• ECG abnormalities 
All adverse events will be coded using applicable dictionaries and summarised by body system 
organ class and preferred term, by intensity and by causal relationship to the Investigational 
Medicinal Product (IMP).  Only those occurrences which occur from the start of IP/IMP 
administration through the follow-up period defined in the protocol will be tabulated in the 
Clinical Trial Report as “adverse events”. 
Concomitant medications will be coded according to therapeutic area using the WHO drug 
reference list. Concomitant medications recorded between signing of informed consent and 
follow-up will be presented in data listings for all subjects dosed.  
Efficacy Analysis  
General 
Efficacy analysis will include the data from all evaluable subjects who are dosed and have 
efficacy data available. Training subjects will not be included in the efficacy analysis. The results 
will be presented for each dose group, if applicable. Except as noted, the statistical tests will be 
two-sided at the 0.05 level of significance with 95% confidence limit. 
Comparison of signal intensity (SI) on BR55 CEUS between two phases of the menstrual cycle  
The objective of this study is to determine the optimal phase of the menstrual cycle for 
performing BR55 CEUS of the target ovary in premenopausal women at high risk for ovarian 
cancer.   
 
The analysis will be performed on subjects determined by pathology to be negative for cancer. 
The descriptive summary of the SI will be presented for early follicular phase and late follicular 
phase of the menstrual cycle. A scatter plot will be graphed to present the distributions of the 
paired observations for the early follicular phase SI versus the late follicular phase SI. The null 
hypothesis that early and late follicular phase imaging time points yield equal SI difference will 
be tested: 
H0: SIearly = SIlate 
Ha: SIearly  ≠  SIlate 
 
If the data at each time point can be normalized, a paired t- test will be performed. Otherwise the 
Wilcoxon signed-rank test will be used.  
Correlation between SI at BR55 CEUS within the target ovary and histopathology findings  
Descriptive statistics will be presented for SI on BR55 CEUS by the histopathology findings.  
Correlation between SI within the target ovary on BR55 CEUS and VEGFR2 expression as 
determined by immunohistochemistry (IHC) 
Descriptive statistics will be presented for the relationship between SI within the target ovary on 
BR55 CEUS and VEGFR2 expression level, as measured by the angiogenesis score. If data are 


Fully Amended Synopsis No. 1 
BR55-109  
Final Version  
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available, Spearman correlation coefficient may be estimated to explore the correlation between 
SI within the target ovary on BR55 CEUS and VEGFR2 expression level. 
Correlation between SI within the target ovary on BR55 CEUS and microvessel density (MVD)  
 
Descriptive statistics will be presented to explore the relationship between the SI within the 
target ovary on BR55 CEUS and MVD. If data are available, Spearman correlation coefficient 
may be estimated to explore the correlation between SI within the target ovary on BR55 CEUS 
and MVD. 
Sample Size 
Since this is the first-in-women clinical trial to determine the optimal phase of the menstrual 
cycle for performing BR55 CEUS of the target ovary in premenopausal women at high risk for 
ovarian cancer, no data exist from which to estimate variability or anticipate effect size, nor are 
there data to indicate a clinically relevant difference. Hence, this is an exploratory study. The 
sample size determination is not based on the statistical considerations and assumptions. About 
50 female subjects meeting inclusion and exclusion criteria will be prospectively enrolled in 
order to obtain 47 evaluable subjects with normal bilateral ovaries and no occult cancer.  
Data Handling 
All data collected will be entered into the database and displayed in the subject data listings. In 
general, no imputation algorithms will be used to estimate missing safety and efficacy data, and 
tables will display counts of missing values. 
Interim Analyses 
No interim analysis is planned.