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

Characterization of Focal Liver Lesions With SONOVUE®-Enhanced Ultrasound Imaging: A Phase III, Intrapatient Comparative Study Versus Un-enhanced Ultrasound Imaging Using Histology or Combined Imaging/Clinical Data as Truth Standard

The purpose of this study is to demonstrate the superiority of SonoVue®-enhanced ultrasound versus unenhanced ultrasound for characterization of Focal Liver Lesions using final diagnosis based on histology or combined imaging/clinical data as truth standard.

Study Overview

• Status: Completed
• Conditions: Liver Neoplasms
• Intervention / Treatment: Drug: SonoVue-enhanced ultrasound; Other: Unenhanced ultrasound

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.

• Study Type: Interventional
• Enrollment (Actual): 349
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • Princeton, New Jersey, United States, 08540
      • Bracco Diagnostics Inc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 focal liver lesion (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 contrast-enhanced (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 beta-human chorionic gonadotropin (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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Other: Patients who received SonoVue; Patients with at least 1 target lesion 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

Drug: SonoVue-enhanced ultrasound; Contrast-enhanced ultrasound (CE-US) examination of the target lesion. Drug: SonoVue® Dose of 2.4 mL bolus injection administered intravenously. Maximum of 2 injections (4.8 mL); Other Names: sulfur hexafluoride microbubbles; Other: Unenhanced ultrasound; -Unenhanced: Gray scale and Doppler (color or power imaging) ultrasound investigations of the target lesion. Drug: None

What is the study measuring?

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 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 the truth standard. Truth standard: contrast-enhanced computed tomography (CE CT) and /or contrast-enhanced magnetic resonance imaging (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 Malignant 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 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	The 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 the truth standard. True negative: subject with a target lesion characterized as benign 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 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 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 ultrasound) x 100.	24 hours to 6 months
Negative Predictive Value (NPV): Percentage of True Negative Lesions Among All Malignant 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 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 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. 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	Inter-reader agreement of assessment of malignant or benign by unenhanced and SonoVue-enhanced ultrasonography separately. Unit of analysis was the lesion, equivalent to the subject, since each subject had a single lesion that was to be characterized. 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

Collaborators and Investigators

• Sponsor: Bracco Diagnostics, Inc
• Investigators: Study Chair: Maria Luigia Storto, M.D., Bracco Diagnostics, Inc

Study record dates

Study Major Dates

• Study Start: September 1, 2009
• Primary Completion (Actual): July 1, 2013
• Study Completion (Actual): July 1, 2013

Study Registration Dates

• First Submitted: November 7, 2008
• First Submitted That Met QC Criteria: November 10, 2008
• First Posted (Estimate): November 11, 2008

Study Record Updates

• Last Update Posted (Actual): December 12, 2017
• Last Update Submitted That Met QC Criteria: November 13, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Digestive System Neoplasms; Liver Diseases; Liver Neoplasms
• Other Study ID Numbers: BR1-128

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No