Neoplasms

Digestive System Diseases

All Conditions

Liver Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Liver Diseases

Hematinics

All Drugs and Chemicals

Liver Extracts

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

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)

SonoVue-enhanced ultrasound

-Unenhanced: Gray scale and Doppler (color or power imaging) ultrasound investigations of the target lesion. Drug: None

Unenhanced ultrasound

Maria Luigia Storto, M.D.

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.

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.

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

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 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.

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.

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.

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.

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.

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.

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".

Bracco Diagnostics, Inc

An AE was defined as any untoward medical occurrence in a patient or a clinical trial subject administered a medicinal product and that did not necessarily have to have a causal relationship with the use of the product. Any patient who received SonoVue is in the Safety Population.

Of 349 patients who started the study, 12 had "No study drug administered" and are not included and 337 received SonoVue and are included in the Safety Population.

All AEs were categorized using MedDRA 12.1.

Interventions included SonoVue administration, unenhanced and SonoVue-enhanced ultrasound and definitive truth standard diagnosis.

Any patient who received SonoVue, training or efficacy phase, regardless of availability of ultrasonography or truth standard, is included in the Safety Population. Twelve patients with "No study drug administered" are not included in the Safety Population.

Of 349 patients who started the study, 12 patients had "No study drug administered" and are not included and 337 received SonoVue and are included in the Safety Population.

Safety Population

All patients who received SonoVue and enrolled in the efficacy phase, had a definite final diagnosis from truth standard and unenhanced and SonoVue-enhanced ultrasonography available

ITD Population

Age, Categorical

Sex: Female, Male

White

Black

Asian

Other

Race/Ethnicity, Customized

United States

Europe

Region of Enrollment

Maria Luigia Storto, MD Executive Director X-Ray and Ultrasound Medical Affairs

Offsite Reader 1 unenhanced (UE) US assessment

Offsite Reader 1 - UE-US

Offsite Reader 1 SonoVue CE-US assessment

Offsite Reader 1 SonoVue CE-US

Offsite Reader 2 - UE-US

Offsite Reader 2 SonoVue CE-US assessment

Offsite Reader 2 SonoVue CE-US

Offsite Reader 3 UE-US

Offsite Reader 3 SonoVue CE-US assessment

Offsite Reader 3 SonoVue CE-US

Among the 240 ITD participants, only 124 participants (lesions) were malignant based on the truth standard and were included for sensitivity.

Sensitivity: Percentage of True Positive Lesions Among All Malignant Lesions Per Truth Standard

Among the 240 ITD participants, only 116 participants (lesions) were benign based on the truth standard and were included for specificity.

Specificity: Percentage of True Negative Lesions Among All Malignant Lesions Per Truth Standard

Accuracy: Percentage of True Positive and True Negative Among All Lesions

Among the 240 ITD participants, the overall number of participants (lesions) assessed as malignant varied based on the evaluation of the UE-US and CE-US made by each off-site Reader.

Positive Predictive Value (PPV): Percentage of True Positive Lesions Among All Malignant Lesions Per Ultrasound

Among the 240 ITD participants, the overall number of participants (lesions) assessed as benign varied based on the evaluation of the UE-US and CE-US made by each off-site Reader.

Negative Predictive Value (NPV): Percentage of True Negative Lesions Among All Malignant Lesions Per Ultrasound

# of HCC by Truth Standard

# HCC(Malignant) Correctly Characterized

# of Metastasis by Truth Standard

# Metastasis Correctly Characterized

Among the 124 ITD participants with malignant lesions based on the truth standard, only 115 participants (lesions) were characterized as either hepatocellular carcinoma (HCC) lesions or metastatic lesions.

Specific Diagnosis of Malignant FLLs

# of Hemangioma by Truth Standard

# Hemangioma Correctly Characterized

# of Focal nodular hyperplasia by Truth Standard

#Focal nodular hyperplasia Correctly Characterized

Among the 116 ITD participants with benign lesions based on the truth standard, only 89 participants (lesions) were characterized as either hemangioma or focal nodular hyperplasia.

Specific Diagnosis of Benign FLLs

% Agreement: All 3 off-site readers agree

% Agreement: 2 out of 3 off-site readers agree

UE-US

CE-US

Inter-reader Agreement

Interventions included SonoVue administration, unenhanced and SonoVue-enhanced ultrasound and definitive truth standard diagnosis.

Any patient who received SonoVue, training or efficacy phase, regardless of availability of ultrasonography or truth standard, is included in the Safety Population. Twelve patients with "No study drug administered" are not included in the Safety Population.

From 337 patients in the Safety Population, 74 patients enrolled in the training phase were excluded from efficacy analysis, and the Completed patients include efficacy phase patients who underwent SonoVue-enhanced ultrasound (SonoVue CE-US), unenhanced ultrasound (UE-US),and had definite truth standard diagnosis available.

Spots Global Cancer Trial Database for SonoVue®-Enhanced Ultrasound Versus Unenhanced US for Focal Liver Lesion Characterization

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