Back to resultsSonoVue®-Enhanced Ultrasound (US) Versus Unenhanced US for Focal Liver Lesion Characterization
Primary Purpose
Liver Neoplasms
Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
SonoVue®
Sponsored by
About this trial
This is an interventional diagnostic trial for Liver Neoplasms
Eligibility Criteria
Inclusion Criteria:
- Male/female.
- Provides written Informed Consent and is willing to comply with protocol requirements.
- Is at least 18 years of age.
- Has at least 1 FLL (target lesion) requiring work-up for characterization. Target lesions may include those:
Incidentally detected, In subjects with chronic hepatitis or liver cirrhosis, In subjects with known history of malignancy.
- Is scheduled for surgical removal or biopsy of the target lesion from 24 hours to 30 days after the SonoVue® administration OR
- In case tissue biopsy is not indicated nor surgery planned, is scheduled for or has performed a CE-CT and/or CE-MRI of the target lesion from 30 days to 48 hours prior to or from 24 hours to 30 days after the administration of SonoVue®.
Exclusion Criteria:
- Has an acoustic window insufficient for adequate ultrasound examination of the liver.
- Has a FLL that cannot be identified with unenhanced ultrasound.
- Has received or is scheduled for antineoplastic chemotherapy or an invasive procedure in the time period between test procedures and truth standard assessments which may have modified the target lesion.
- Is receiving any other contrast medium, within the 48 hours before and up to 24 hours following the administration of SonoVue®.
- Has previously been enrolled in and completed this study.
- Known right to left cardiac shunt, bidirectional or transient.
- Has any known allergy to 1 or more of the ingredients of the investigational product (sulfur hexafluoride or to any components of SonoVue®).
- Has any contraindication to 1 of the planned imaging procedures (ultrasound, CT or MRI), e.g., implants, claustrophobia, inadequate medical conditions etc.
- Has received an investigational compound within 30 days before admission into this study.
- Has any medical condition or other circumstances which would significantly decrease the chances of obtaining reliable data, achieving study objectives, or completing the study and/or post-dose follow-up examinations.
- Is determined by the Investigator that the subject is clinically unsuitable for the study.
- Is a pregnant or lactating female. Exclude the possibility of pregnancy by:
testing on site at the institution serum βHCG within 24 hours prior to the start of SonoVue® administration, surgical history (e.g., tubal ligation or hysterectomy), post menopausal with a minimum 1 year without menses.
Sites / Locations
- Bracco Diagnostics Inc.
Arms of the Study
Arm 1
Arm Type
Other
Arm Label
Patients who received SonoVue
Arm Description
Patients with at least one target lesions requiring work-up for characterization to undergo Unenhanced ultrasound of the target lesion (UE-US): gray scale and Doppler (color or power imaging) ultrasound investigations of the target lesion using commercially available ultrasound equipment and standard techniques (B-mode or Harmonic imaging) to study the anatomy of the target lesion and surrounding parenchyma; SonoVue-enhanced ultrasound of the target lesion (CE-US):procedures described in protocol Section 7.5.1.2, to study the lesion vascularity in comparison to the surrounding parenchyma; and Truth standard 2.4 mL of sulfur hexafluoride microbubbles (SonoVue®) will be administered as a bolus injection in a peripheral vein.
Outcomes
Primary Outcome Measures
Sensitivity: Percentage of True Positive Lesions Among All Malignant Lesions Per Truth Standard
Sensitivity of SonoVue-enhanced ultrasound (SonoVue CE-US) versus unenhanced ultrasound (UE-US) for characterization of malignant focal liver lesions (FLLs) using the diagnosis provided by each of the 3 off-site assessors (blinded to patient data) for the Intent-to-diagnose (ITD) population. Unit of analysis was the lesion, equivalent to subject, since each subject had a single lesion to be characterized.
True positive: subject with a target lesion characterized as malignant by both ultrasonography and the truth standard.
Truth standard: CE-CT and/or CE-MRI examination OR tissue pathology/histology from surgical resection/biopsy OR 6-month follow up Calculated as (number of true positive lesions/number of malignant lesions per truth standard) x 100
Specificity: Percentage of True Negative Lesions Among All Benign Lesions Per Truth Standard'
Specificity of SonoVue-enhanced versus unenhanced ultrasound for characterization of benign FLLs, using the diagnosis provided by each of the 3 off-site assessors (blinded to patient data) for the ITD population.
Unit of analysis was the lesion, equivalent to the subject, since each subject had a single lesion that was to be characterized.
True negative: subject with a target lesion characterized as benign by both ultrasonography and truth standard.
Among the 259 ITD participants, only 140 participants (lesions) were benign based on the truth standard.
Truth standard: CE-CT and /or CE-MRI examination OR tissue pathology/histology from surgical resection/biopsy OR 6-month follow up. Calculated as (number of true negative lesions/number of benign lesions per truth standard) x 100.
Secondary Outcome Measures
Accuracy: Percentage of True Positive and True Negative Among All Lesions
Accuracy of SonoVue-enhanced versus unenhanced ultrasound for characterization of malignant and benign FLLs, using the diagnosis provided by each of the 3 off-site assessors (blinded to patient data) for the ITD population.
Unit of analysis was the lesion, equivalent to the subject, since each subject had a single lesion that was to be characterized.
True positive: subject with a target lesion characterized as malignant by both ultrasonography and truth standard.
True negative: subject with a target lesion characterized as benign by both ultrasonography and truth standard.
Truth standard: CE-CT and /or CE-MRI examination OR tissue pathology/histology from surgical resection/biopsy OR 6-month follow up. Calculated as (number of true positive and true negative lesions/number of total lesions per truth standard) x 100.
Positive Predictive Value [PPV]: Percentage of True Positive Lesions Among All Malignant Lesions Per Ultrasound
Positive Predictive Value of SonoVue-enhanced versus unenhanced ultrasound for characterization of FLLs, using the diagnosis provided by each of the 3 off-site assessors (blinded to patient data) for the ITD population. Unit of analysis was the lesion, equivalent to the subject, since each subject had a single lesion that was to be characterized.
True positive: subject with a target lesion characterized as malignant by both ultrasonography and truth standard.
Truth standard: CE-CT and /or CE-MRI examination OR tissue pathology/histology from surgical resection/biopsy OR 6-month follow up.
Calculated as (number of true positive lesions/number of malignant lesions per ultrasound) x 100.
Negative Predictive Value [NPV]: Percentage of True Negative Lesions Among All Benign Lesions Per Ultrasound
Negative Predictive Value of SonoVue-enhanced versus unenhanced ultrasound for characterization of FLLs, using the diagnosis provided by each of the 3 off-site assessors (blinded to patient data) for the ITD population. Unit of analysis was the lesion, equivalent to the subject, since each subject had a single lesion that was to be characterized.
True negative: subject with a target lesion characterized as benign by both ultrasonography and truth standard.
Truth standard: CE-CT and /or CE-MRI examination OR tissue pathology/histology from surgical resection/biopsy OR 6-month follow up. Calculated as (number of true negative lesions/number of benign lesions per ultrasound) x 100.
Specific Diagnosis of Malignant FLLs
SonoVue-enhanced versus unenhanced ultrasound for specific diagnosis of malignant FLLs, using the diagnosis provided by each of the 3 off-site assessors (blinded to patient data) for the ITD population. Unit of analysis was the lesion, equivalent to the subject, since each subject had a single lesion that was to be characterized.
Truth standard: CE-CT and /or CE-MRI examination OR tissue pathology/histology from surgical resection/biopsy OR 6-month follow up. Calculated as (number of correctly characterized lesions/number of lesions per truth standard) x 100.
Specific Diagnosis of Benign FLLs
SonoVue-enhanced versus unenhanced ultrasound for specific diagnosis of benign FLLs, using the diagnosis provided by each of the 3 off-site assessors (blinded to patient data) for the ITD population. Unit of analysis was the lesion, equivalent to the subject, since each subject had a single lesion that was to be characterized.
Among the 140 ITD participants with benign lesions based on the truth standard, only 91 participants (lesions) were characterized as either hemangioma or focal nodular hyperplasia.
Truth standard: CE-CT and /or CE-MRI examination OR tissue pathology/histology from surgical resection/biopsy OR 6-month follow up. Calculated as (number of correctly characterized lesions/number of lesions per truth standard) x 100.
Inter-reader Agreement
Kappa statistic based on assessment of malignant or benign by unenhanced and SonoVue-enhanced ultrasonography separately and computation for the percentage agreement within two categories: "3 out of 3 readers agree" and "2 out of 3 readers agree".
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT00829413
Brief Title
SonoVue®-Enhanced Ultrasound (US) Versus Unenhanced US for Focal Liver Lesion Characterization
Official Title
Characterization Of Focal Liver Lesions With Sonovue®-Enhanced Ultrasound Imaging: A Phase III, Intrapatient Comparative Study Versus Unenhanced Ultrasound Imaging Using Histology Or Combined Imaging/Clinical Data As Truth Standard
Study Type
Interventional
2. Study Status
Record Verification Date
November 2017
Overall Recruitment Status
Completed
Study Start Date
June 2010 (undefined)
Primary Completion Date
July 2013 (Actual)
Study Completion Date
July 2013 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bracco Diagnostics, Inc
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
The purpose of this study is to demonstrate the Sensitivity and Specificity of SonoVue®-enhanced ultrasound is superior to that of unenhanced ultrasound for the characterization of benign versus malignant FLLs using final diagnosis based on histology or combined imaging (CE-CT and/or CE MRI)/clinical data as truth standard.
Detailed Description
Unit of analysis for the outcome measures was the lesion, equivalent to the subject, since each subject had a single lesion that was to be characterized.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Liver Neoplasms
7. Study Design
Primary Purpose
Diagnostic
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
353 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Patients who received SonoVue
Arm Type
Other
Arm Description
Patients with at least one target lesions requiring work-up for characterization to undergo
Unenhanced ultrasound of the target lesion (UE-US): gray scale and Doppler (color or power imaging) ultrasound investigations of the target lesion using commercially available ultrasound equipment and standard techniques (B-mode or Harmonic imaging) to study the anatomy of the target lesion and surrounding parenchyma;
SonoVue-enhanced ultrasound of the target lesion (CE-US):procedures described in protocol Section 7.5.1.2, to study the lesion vascularity in comparison to the surrounding parenchyma; and
Truth standard
2.4 mL of sulfur hexafluoride microbubbles (SonoVue®) will be administered as a bolus injection in a peripheral vein.
Intervention Type
Drug
Intervention Name(s)
SonoVue®
Other Intervention Name(s)
sulfur hexafluoride microbubbles
Intervention Description
SonoVue (2.4 mL)
Primary Outcome Measure Information:
Title
Sensitivity: Percentage of True Positive Lesions Among All Malignant Lesions Per Truth Standard
Description
Sensitivity of SonoVue-enhanced ultrasound (SonoVue CE-US) versus unenhanced ultrasound (UE-US) for characterization of malignant focal liver lesions (FLLs) using the diagnosis provided by each of the 3 off-site assessors (blinded to patient data) for the Intent-to-diagnose (ITD) population. Unit of analysis was the lesion, equivalent to subject, since each subject had a single lesion to be characterized.
True positive: subject with a target lesion characterized as malignant by both ultrasonography and the truth standard.
Truth standard: CE-CT and/or CE-MRI examination OR tissue pathology/histology from surgical resection/biopsy OR 6-month follow up Calculated as (number of true positive lesions/number of malignant lesions per truth standard) x 100
Time Frame
24 hours to 6 months
Title
Specificity: Percentage of True Negative Lesions Among All Benign Lesions Per Truth Standard'
Description
Specificity of SonoVue-enhanced versus unenhanced ultrasound for characterization of benign FLLs, using the diagnosis provided by each of the 3 off-site assessors (blinded to patient data) for the ITD population.
Unit of analysis was the lesion, equivalent to the subject, since each subject had a single lesion that was to be characterized.
True negative: subject with a target lesion characterized as benign by both ultrasonography and truth standard.
Among the 259 ITD participants, only 140 participants (lesions) were benign based on the truth standard.
Truth standard: CE-CT and /or CE-MRI examination OR tissue pathology/histology from surgical resection/biopsy OR 6-month follow up. Calculated as (number of true negative lesions/number of benign lesions per truth standard) x 100.
Time Frame
24 hours to 6 months
Secondary Outcome Measure Information:
Title
Accuracy: Percentage of True Positive and True Negative Among All Lesions
Description
Accuracy of SonoVue-enhanced versus unenhanced ultrasound for characterization of malignant and benign FLLs, using the diagnosis provided by each of the 3 off-site assessors (blinded to patient data) for the ITD population.
Unit of analysis was the lesion, equivalent to the subject, since each subject had a single lesion that was to be characterized.
True positive: subject with a target lesion characterized as malignant by both ultrasonography and truth standard.
True negative: subject with a target lesion characterized as benign by both ultrasonography and truth standard.
Truth standard: CE-CT and /or CE-MRI examination OR tissue pathology/histology from surgical resection/biopsy OR 6-month follow up. Calculated as (number of true positive and true negative lesions/number of total lesions per truth standard) x 100.
Time Frame
24 hours to 6 months
Title
Positive Predictive Value [PPV]: Percentage of True Positive Lesions Among All Malignant Lesions Per Ultrasound
Description
Positive Predictive Value of SonoVue-enhanced versus unenhanced ultrasound for characterization of FLLs, using the diagnosis provided by each of the 3 off-site assessors (blinded to patient data) for the ITD population. Unit of analysis was the lesion, equivalent to the subject, since each subject had a single lesion that was to be characterized.
True positive: subject with a target lesion characterized as malignant by both ultrasonography and truth standard.
Truth standard: CE-CT and /or CE-MRI examination OR tissue pathology/histology from surgical resection/biopsy OR 6-month follow up.
Calculated as (number of true positive lesions/number of malignant lesions per ultrasound) x 100.
Time Frame
24 hours to 6 months
Title
Negative Predictive Value [NPV]: Percentage of True Negative Lesions Among All Benign Lesions Per Ultrasound
Description
Negative Predictive Value of SonoVue-enhanced versus unenhanced ultrasound for characterization of FLLs, using the diagnosis provided by each of the 3 off-site assessors (blinded to patient data) for the ITD population. Unit of analysis was the lesion, equivalent to the subject, since each subject had a single lesion that was to be characterized.
True negative: subject with a target lesion characterized as benign by both ultrasonography and truth standard.
Truth standard: CE-CT and /or CE-MRI examination OR tissue pathology/histology from surgical resection/biopsy OR 6-month follow up. Calculated as (number of true negative lesions/number of benign lesions per ultrasound) x 100.
Time Frame
24 hours to 6 months
Title
Specific Diagnosis of Malignant FLLs
Description
SonoVue-enhanced versus unenhanced ultrasound for specific diagnosis of malignant FLLs, using the diagnosis provided by each of the 3 off-site assessors (blinded to patient data) for the ITD population. Unit of analysis was the lesion, equivalent to the subject, since each subject had a single lesion that was to be characterized.
Truth standard: CE-CT and /or CE-MRI examination OR tissue pathology/histology from surgical resection/biopsy OR 6-month follow up. Calculated as (number of correctly characterized lesions/number of lesions per truth standard) x 100.
Time Frame
24 hours to 6 months
Title
Specific Diagnosis of Benign FLLs
Description
SonoVue-enhanced versus unenhanced ultrasound for specific diagnosis of benign FLLs, using the diagnosis provided by each of the 3 off-site assessors (blinded to patient data) for the ITD population. Unit of analysis was the lesion, equivalent to the subject, since each subject had a single lesion that was to be characterized.
Among the 140 ITD participants with benign lesions based on the truth standard, only 91 participants (lesions) were characterized as either hemangioma or focal nodular hyperplasia.
Truth standard: CE-CT and /or CE-MRI examination OR tissue pathology/histology from surgical resection/biopsy OR 6-month follow up. Calculated as (number of correctly characterized lesions/number of lesions per truth standard) x 100.
Time Frame
24 hours to 6 months
Title
Inter-reader Agreement
Description
Kappa statistic based on assessment of malignant or benign by unenhanced and SonoVue-enhanced ultrasonography separately and computation for the percentage agreement within two categories: "3 out of 3 readers agree" and "2 out of 3 readers agree".
Time Frame
24 hours to 6 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Male/female.
Provides written Informed Consent and is willing to comply with protocol requirements.
Is at least 18 years of age.
Has at least 1 FLL (target lesion) requiring work-up for characterization. Target lesions may include those:
Incidentally detected, In subjects with chronic hepatitis or liver cirrhosis, In subjects with known history of malignancy.
Is scheduled for surgical removal or biopsy of the target lesion from 24 hours to 30 days after the SonoVue® administration OR
In case tissue biopsy is not indicated nor surgery planned, is scheduled for or has performed a CE-CT and/or CE-MRI of the target lesion from 30 days to 48 hours prior to or from 24 hours to 30 days after the administration of SonoVue®.
Exclusion Criteria:
Has an acoustic window insufficient for adequate ultrasound examination of the liver.
Has a FLL that cannot be identified with unenhanced ultrasound.
Has received or is scheduled for antineoplastic chemotherapy or an invasive procedure in the time period between test procedures and truth standard assessments which may have modified the target lesion.
Is receiving any other contrast medium, within the 48 hours before and up to 24 hours following the administration of SonoVue®.
Has previously been enrolled in and completed this study.
Known right to left cardiac shunt, bidirectional or transient.
Has any known allergy to 1 or more of the ingredients of the investigational product (sulfur hexafluoride or to any components of SonoVue®).
Has any contraindication to 1 of the planned imaging procedures (ultrasound, CT or MRI), e.g., implants, claustrophobia, inadequate medical conditions etc.
Has received an investigational compound within 30 days before admission into this study.
Has any medical condition or other circumstances which would significantly decrease the chances of obtaining reliable data, achieving study objectives, or completing the study and/or post-dose follow-up examinations.
Is determined by the Investigator that the subject is clinically unsuitable for the study.
Is a pregnant or lactating female. Exclude the possibility of pregnancy by:
testing on site at the institution serum βHCG within 24 hours prior to the start of SonoVue® administration, surgical history (e.g., tubal ligation or hysterectomy), post menopausal with a minimum 1 year without menses.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alberto Spinazzi, M.D.
Organizational Affiliation
Bracco Diagnostics, Inc
Official's Role
Study Director
Facility Information:
Facility Name
Bracco Diagnostics Inc.
City
Princeton
State/Province
New Jersey
ZIP/Postal Code
08540
Country
United States
12. IPD Sharing Statement
Learn more about this trial
SonoVue®-Enhanced Ultrasound (US) Versus Unenhanced US for Focal Liver Lesion Characterization
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