SonoVue®-Enhanced Ultrasound (US) Versus Unenhanced US for Focal Liver Lesion Characterization

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Liver Neoplasms

Intervention / Treatment
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* Drug: SonoVue®


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Patients who received SonoVue<br>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. | Drug: SonoVue®<br>* SonoVue (2.4 mL)<br>* Other names: sulfur hexafluoride microbubbles;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 24 hours to 6 months | 
| 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. | 24 hours to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 24 hours to 6 months | 
| 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. | 24 hours to 6 months | 
| 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. | 24 hours to 6 months | 
| 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. | 24 hours to 6 months | 
| 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. | 24 hours to 6 months | 
| 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. | 24 hours to 6 months |