An Efficacy and Safety Study of Sonazoid™ and SonoVue® in Participants With Focal Liver Lesions, Undergoing Pre- and Post-Contrast Ultrasound Imaging

Study Overview
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Brief Summary
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The purpose of this study is to compare the efficacy of Sonazoid™ and SonoVue® in participants with focal liver lesions (FLLs), by comparing pre-and post-contrast ultrasound examination findings with regard to various aspects of lesion diagnosis including diagnosis as benign versus malignant, specific lesion diagnosis, confidence in diagnosis, and quality of delineation of lesion-related blood vessels (from images obtained during vascular imaging) and detection of lesion presence and quality of delineation of the whole liver (from images obtained during whole liver imaging).

Official Title
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A Phase 3 Multicentre, Randomised, Comparative Study of the Efficacy and Safety of the Ultrasound Contrast Agents Sonazoid™ and SonoVue® in Subjects With Focal Liver Lesions Undergoing Pre- and Post-Contrast Ultrasound Imaging

Conditions
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Liver Lesions

Intervention / Treatment
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* Drug: Sonazoid™
* Drug: SonoVue®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants may be included in the study if they meet all of the following criteria: Participant has at least 1 untreated focal liver lesions (FLL) but =<8 lesions (excluding cysts) <10 centimeter (cm) in diameter confirmed in a diagnostic examination performed in the past month (or past 3 months if lesion is benign) that can be visualised by non- contrast-enhanced (CE) ultrasound Participant has had a dynamic CE-computed tomography (CE-CT) or CE-magnetic resonance imaging (CE-MRI) examination within the past month or is scheduled to have one in the month following inclusion in the study and the original images (or copies thereof) are/will be available. (This inclusion criterion does not apply for participants enrolled as training cases. Investigators will be asked to submit standard of truth/ reference diagnosis for training cases whenever possible, since the cases may be used for training and testing the blinded readers prior to the blinded read) Participant is a 20- to 80-year-old inpatient or outpatient referred for an ultrasound examination of the liver Participant is able and willing to comply with study procedures and will give their signed and dated informed consent The participant, if female, is either surgically sterile (has had a documented bilateral oophorectomy and/or documented hysterectomy), postmenopausal (cessation of menses for more than 1 year), or non-lactating, or if of childbearing potential the results of a serum or urine human chorionic gonadotropin pregnancy test, performed on the day of investigational medicinal product (IMP) administration (with the result known before IMP administration), are negative Exclusion Criteria: The participant has an acute clinically fatal condition (i.e., not expected to survive for at least 6 months) The participant has previously received Sonazoid™ or has received SonoVue® within the past 30 days The participant has undergone or is undergoing systemic or loco-regional chemotherapy, or radiation therapy The participant is participating in another clinical trial with an unregistered medicinal product, or less than 30 days have passed since completing participation in such a trial The participant has a history of allergies to eggs or egg products (i.e., manifested by full body rash, respiratory difficulty, oral or laryngeal swelling, hypotension or shock) The participant has known hypersensitivity to sulphur hexafluoride or to any of the components of SonoVue® The participant has undergone or plans to undergo liver biopsy or surgery within the 24 hours before or after this examination The participant has undergone or plans to undergo an examination with a contrast agent (i.e., iodinated x-ray contrast agent, magnetic resonance imaging (MRI) contrast agent or another ultrasound contrast agent) within the 24 hours before or after this examination The participant is considered to be unsuitable to participate in the study by the investigator The participant is known to have a right-to-left shunt, severe pulmonary hypertension (pulmonary artery pressure >90 millimeter of mercury (mmHg) or uncontrolled systemic hypertension The participant has a recent acute coronary syndrome or clinically unstable ischaemic cardiac disease, including: evolving or ongoing myocardial infarction, typical angina at rest within the last 7 days, significant worsening of cardiac symptoms within the last 7 days, recent coronary artery intervention or other factors suggesting clinical instability (e.g., recent deterioration of electrocardiogram [ECG], laboratory or clinical findings), acute cardiac failure, Class III/IV cardiac failure, or severe rhythm disorders The participant has adult respiratory distress syndrome, severe emphysema, pulmonary vasculitis, or a history of pulmonary emboli The participant has known thrombosis within the liver, portal, or mesenteric veins

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 80 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sonazoid™<br>Participants will receive single intravenous (I.V) bolus injection of Sonazoid™ 0.12 microliter (µL) microbubbles (MB)/kilogram (kg) body weight. | Drug: Sonazoid™<br>* Single Dose of Sonazoid™ 0.12 µL MB/kg as I.V. injection.<br>|
| Active Comparator: SonoVue®<br>Participants will receive single I.V bolus injection of SonoVue® 2.4 milliliter (mL). | Drug: SonoVue®<br>* Single Dose of SonoVue® 2.4 mL as I.V. injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Accuracy Improvement in Post-Contrast Versus Pre-Contrast Ultrasound (US) Examination for Diagnosis of the Target Lesion as Malignant or Benign Against the Reference Diagnosis (RD)/Standard of Truth | Accuracy improvement was calculated by the number of participants with improved diagnoses from the pre-contrast diagnosis to the post-contrast diagnosis divided by the total number of participants, multiplied by 100. Assessments were done by 3 blinded readers. Efficacy population which included all participants who received Sonazoid™ or SonoVue®, for whom pre-contrast & post-contrast images were recorded, & for whom there was a reference standard contrast-enhanced computed tomography (CECT)/contrast-enhanced magnetic resonance imaging (CE-MRI) examination or biopsy. | Pre-administration up to 15 minutes post-administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Lesions Detected by Post-Contrast US Relative to Number of Lesions Detected by Pre-Contrast US (Both by Blinded Readers[BR]) and Number of Lesions Detected by Post-Contrast US (by BR) Relative to Number of Lesions Detected by RD (Investigators) | For the cases that can be assessed by the blinded readers both pre- and post-contrast, differences were calculated between the Sonazoid™ and SonoVue® groups in the number of lesions detected during whole-liver imaging (post-contrast minus pre-contrast). The differences were also calculated between the Sonazoid™ and SonoVue® groups in the number of lesions (post-contrast minus reference diagnosis) detected during whole-liver imaging. | Pre-administration up to 15 minutes post-administration | 
| Number of Participants With Diagnostic Confidence (Evaluated by Blinded Readers) in Pre-Contrast and Post-Contrast Ultrasound Examination Results | Confidence in diagnoses from the pre- and post-contrast ultrasound examinations was evaluated based on 4-point scale: 0-Unknown (cannot make a judgement on level of confidence), 1- Not confident (another examination was required), 2- Probable (Would have more confidence if another diagnostic imaging test such as MRI or CT was performed), 3- Definite (Sufficient confidence to the extent that another diagnostic imaging test such as MRI or CT was unnecessary). | Pre-administration up to 15 minutes post-administration | 
| Percentage of Participants With Accuracy Improvement in Post-contrast Versus Pre-contrast Ultrasound Examination for Lesion-Specific Diagnoses of the Target Lesion Against the Reference Diagnosis/Standard of Truth | The accuracy improvement was calculated by the number of participants with improved diagnoses from the pre-contrast diagnosis to the post-contrast diagnosis divided by the total number of participants, multiplied by 100. Assessment was performed by 3 blinded readers. | Pre-administration up to 15 minutes post-administration |