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

Phase 3

Completed

• Conditions: Liver Neoplasms
• Interventions: Drug: SonoVue-enhanced ultrasound; Other: Unenhanced ultrasound

• Registration Number: NCT00788697
• Lead Sponsor: Bracco Diagnostics, Inc

Brief Summary

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.

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 Timeline

• Study First Submitted: 2008-11-07
• Study First Submitted QC: 2008-11-10
• Study First Posted: 2008-11-11
• Study Start: 2009-09
• Primary Completion: 2013-07
• Study Completion: 2013-07
• Disposition First Submitted: 2014-08-18
• Disposition First Submitted QC: 2014-08-19
• Disposition First Posted: 2014-08-21
• Results First Submitted: 2016-09-28
• Results First Submitted QC: 2017-05-17
• Results First Posted: 2017-06-14
• Status Verified: 2017-11
• Last Update Submitted: 2017-11-13
• Last Update Posted: 2017-12-12

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 349

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Patients who received SonoVue	SonoVue-enhanced ultrasound	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
Patients who received SonoVue	Unenhanced ultrasound	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

Primary Outcome Measures

Name	Time	Method
Sensitivity: Percentage of True Positive Lesions Among All Malignant Lesions Per Truth Standard	24 hours to 6 months	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.
Specificity: Percentage of True Negative Lesions Among All Malignant Lesions Per Truth Standard	24 hours to 6 months	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.

Secondary Outcome Measures

Name	Time	Method
Negative Predictive Value (NPV): Percentage of True Negative Lesions Among All Malignant Lesions Per Ultrasound	24 hours to 6 months	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.
Positive Predictive Value (PPV): Percentage of True Positive Lesions Among All Malignant Lesions Per Ultrasound	24 hours to 6 months	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.
Inter-reader Agreement	24 hours to 6 months	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".
Specific Diagnosis of Benign FLLs	24 hours to 6 months	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.
Accuracy: Percentage of True Positive and True Negative Among All Lesions	24 hours to 6 months	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.
Specific Diagnosis of Malignant FLLs	24 hours to 6 months	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.

Trial Locations

Locations (1)

Bracco Diagnostics Inc; 🇺🇸 Princeton, New Jersey, United States