Evaluation of Safety and Efficacy of Lumason/SonoVue in Subjects Undergoing Pharmacologic Stress BR1-141

• Sponsor: Bracco Diagnostics, Inc (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02522481
• Collaborator: (none)
• Enrollment: 175
• Locations: 17
• Arm: 1
• Actual Duration (Months): 29.1
• Patients Per Site: 10.3
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The purpose of this study was to assess the safety and efficacy of Lumason-enhanced dobutamine stress echo (CE-DSE) in subjects having a suboptimal left ventricular endocardial border delineation (LV EBD) at rest and who were scheduled for coronary angiography.

Condition or Disease	Intervention/Treatment	Phase
Coronary Artery Disease	Drug: Lumason	Phase 3

Detailed Description

The study was designed to assess the safety and efficacy of Lumason at improving the visualization of the LV EBD during pharmacologic stress echocardiography examinations and for detection or exclusion of the coronary artery disease (CAD). The study population consisted of adult subjects referred for pharmacological stress echocardiography and with suboptimal image quality during unenhanced ultrasound imaging at rest who had known or suspected CAD. Subjects enrolled in the study represented subjects who could benefit most from contrast-enhanced ultrasound (CEUS) stress echocardiography.

Study Design

• Study Type: Interventional
• Actual Enrollment: 175 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Diagnostic
• Official Title: A Prospective Multicenter Phase III Clinical Evaluation of the Safety and Efficacy of Lumason™/SonoVue® in Subjects Undergoing Pharmacologic Stress Echocardiography With Dobutamine for the Diagnosis of Coronary Artery Disease
• Actual Study Start Date: Sep 24, 2015
• Actual Primary Completion Date: Nov 7, 2017
• Actual Study Completion Date: Feb 25, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lumason Lumason (sulfur hexafluoride lipid-type A microspheres) 2 mL IV injection	Drug: Lumason; Lumason (sulfur hexafluoride-type A microspheres) an ultrasound contrast agent was administered as 2 single 2-mL IV injections during rest and stress echocardiography; Other Names: SonoVue

Outcome Measures

Primary Outcome Measures

1. Sensitivity and Specificity for Detection or Exclusion of Coronary Artery Disease (CAD) [Participants were followed until they had coronary angiography or up to 6 months post dose to collect clinical information on cardiac events if no coronary angiography were performed]

   The diagnostic performance of the echocardiographic images was compared to the truth standard to determine sensitivity and specificity. A diagnosis of coronary artery disease (CAD) was determined for both the echo images and truth standard (positive diagnosis for CAD is defined as >/= 50% stenosis of any vessel on coronary angiography or if no coronary angiography is performed the occurence of a cardiac event based on clinical information for up to 6 months post dose; otherwise the diagnosis is negative). Results for sensitivity and specificity are reflected based on difference between contrast enhanced stress echo and unenhanced stress echo. Results for analysis of data based on majority assessment from the three off-site blinded readers are presented. Sensitivity and specificity are the percentages of correctly diagnosed subjects by stress echo over the total positive and negative subjects according to the truth standard respectively.

2. Reader-Specific Percentages of Participants Identified as Having a Critical Shift From Suboptimal to Optimal Echocardiographic Images [Participants were followed until they had coronary angiography or up to 6 months post dose to collect clinical information on cardiac events if no coronary angiography was performed]

   The percentage of subjects with suboptimal images (defined as >= 2 adjacent segments with inadequate left ventricular endocardial border delineation (LV EBD) in any of the 3 apical views) at unenhanced stress echo converted to adequate (reduction of suboptimal segments in any of the 3 apical views) at contrast-enhanced stress echo

Secondary Outcome Measures

1. Change in Total LV EBD [Participants were followed until they had coronary angiography or up to 6 months post dose to collect clinical information on cardiac events if no coronary angiography was performed]

   Measured as the change in the total LV EBD score based on the 17 segments, from peak stress unenhanced vs. peak stress contrast-enhanced. Total LV EBD score ranges from 0 to 34 and higher score is better outcome.

2. Number of Participants With Adverse Events [up to 72 hours post dose]

   To obtain safety data in subjects administered Lumason during echocardiography

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Provided written Informed Consent and was willing to comply with protocol requirements;

• Was at least 18 years of age;

• Had suspected or known CAD and was scheduled to undergo coronary angiography within 6 months after the LUMASON DSE.

• Had undergone a previous echocardiography prior to enrollment; resulting in suboptimal unenhanced images at rest, defined as ≥ 2 suboptimal adjacent segments in any apical view.

Exclusion Criteria:

• Was a pregnant or lactating female. Excluded the possibility of pregnancy by testing on site at the institution (serum or urine βHCG) within 24 hours prior to the start of LUMASON administration(s), by surgical history (e.g., tubal ligation or hysterectomy), post menopausal with a minimum 1 year without menses;

• Had any known hypersensitivity to 1 or more ingredients of LUMASON (sulfur hexafluoride or to any components of LUMASON);

• Had any known hypersensitivity to dobutamine;

• Had an ongoing or recent (within the last 30 days) acute myocardial infarction;

• Had known right-to-left, bidirectional or transient cardiac shunt (ruled out with agitated saline study performed before administration of LUMASON);

• Had electrolyte (especially potassium and magnesium) abnormalities;

• Had unstable pulmonary and/or systemic hemodynamic conditions e.g.:

• decompensated or inadequately controlled congestive heart failure (NYHA Class IV);

• hypovolemia;

• uncontrolled hypertension, i.e. resting systolic blood pressure >200 mmHg or diastolic blood pressure >110 mmHg;

• unstable angina;

• acute coronary syndrome;

• aortic dissection;

• acute pericarditis,

• myocarditis, or endocarditis;

• stenosis of the main left coronary artery;

• hemodynamically significant outflow obstruction of the left ventricle, including hypertrophic obstructive cardiomyopathy;

• hemodynamically significant cardiac valvular defect;

• acute pulmonary embolism;

• Had uncontrolled cardiac arrhythmias;

• Had significant disturbance in conduction;

• Had hypertrophic subaortic stenosis;

• Had an acute illness (e.g., infections, hyperthyroidism, or severe anemia);

• Was previously entered into this study or received an investigational compound within 30 days before admission into this study;

• Had been treated with any other contrast agent either intravascularly or orally within 48 hours of the first LUMASON administration;

• Had 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 postdose follow-up examinations;

In addition, due to the use of Atropine in subjects who had not reached targeted heart rate with peak dobutamine infusion, subjects with the following were excluded:

• Glaucoma;

• Pyloric stenosis;

• Prostatic hypertrophy.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sarver Heart Center, University of Arizona	Tucson	Arizona	United States	85724
2	University of California San Diego	La Jolla	California	United States	92037
3	Interventional Cardiology Medical Group, Inc.	West Hills	California	United States	91037
4	Cardiology Physicians, PA	Newark	Delaware	United States	19713
5	Community Heart and Vascular Community Hospital East	Indianapolis	Indiana	United States	46250
6	St. Luke's Mid-America Heart Institute	Kansas City	Missouri	United States	64111
7	North Kansas City Hospital	North Kansas City	Missouri	United States	64116
8	Morristown Medical Center	Morristown	New Jersey	United States	07960
9	The Institute for Clinical Research Holy Name Medical Center	Teaneck	New Jersey	United States	07666
10	Mount Sinai Medical Center	New York	New York	United States	10029
11	Mazankowski Alberta Heart Institute, University of Alberta Hospital	Edmonton	Alberta	Canada	T6G2B7
12	Medizinische Klinik m.S. Kardiologie und Angiologie, Charité Universitätsmedizin Berlin	Berlin		Germany	10117
13	Klinikum Lünen, St. Marien-Hospital GmbH	Lünen		Germany	44534
14	Universitätsmedizin Mainz	Mainz		Germany	55131
15	Kardiologie Klinik Dr. Müller GmbH, Peter Osypka Heart Center	Munich		Germany	81379
16	Azienda Ospedaliera Universitaria Parma	Parma		Italy	43126
17	Azienda Policlinico Umberto I Università degli Studi di Roma La Sapienza	Rome		Italy	00161

Sponsors and Collaborators

• Bracco Diagnostics, Inc

Investigators

• Study Director: Melda Dolan, MD, Bracco Diagnostics, Inc

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 30, 2015

More Information

Publications

None provided.

• Responsible Party: Bracco Diagnostics, Inc
• ClinicalTrials.gov Identifier: NCT02522481
• Other Study ID Numbers: BR1-141
• First Posted: Aug 13, 2015
• Last Update Posted: Jun 11, 2021
• Last Verified: Jun 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Bracco Diagnostics, Inc: Lumason; Dobutamine stress echo; stress echo; coronary artery disease
• Additional relevant MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease

Study Results

Participant Flow

Arm/Group Title	Lumason
Arm/Group Description	Lumason (sulfur hexafluoride lipid-type A microspheres) 2 mL IV injection Lumason: Lumason (sulfur hexafluoride-type A microspheres) an ultrasound contrast agent was administered as 2 single 2-mL IV injections during rest and stress echocardiography
Period Title: Overall Study
STARTED	175
COMPLETED	172
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Lumason
Arm/Group Description	Lumason (sulfur hexafluoride lipid-type A microspheres) 2 mL IV injection Lumason: Lumason (sulfur hexafluoride-type A microspheres) an ultrasound contrast agent was administered as 2 single 2-mL IV injections during rest and stress echocardiography
Overall Participants	173
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	76 43.9%
>=65 years	97 56.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.0 (10.47)
Sex: Female, Male (Count of Participants)
Female	52 30.1%
Male	121 69.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	5 2.9%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	4 2.3%
White	160 92.5%
More than one race	4 2.3%
Unknown or Not Reported	0 0%
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	30.33 (7.252)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	169.3 (10.49)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	86.99 (21.781)

Outcome Measures

1. Primary Outcome

Title	Sensitivity and Specificity for Detection or Exclusion of Coronary Artery Disease (CAD)
Description	The diagnostic performance of the echocardiographic images was compared to the truth standard to determine sensitivity and specificity. A diagnosis of coronary artery disease (CAD) was determined for both the echo images and truth standard (positive diagnosis for CAD is defined as >/= 50% stenosis of any vessel on coronary angiography or if no coronary angiography is performed the occurence of a cardiac event based on clinical information for up to 6 months post dose; otherwise the diagnosis is negative). Results for sensitivity and specificity are reflected based on difference between contrast enhanced stress echo and unenhanced stress echo. Results for analysis of data based on majority assessment from the three off-site blinded readers are presented. Sensitivity and specificity are the percentages of correctly diagnosed subjects by stress echo over the total positive and negative subjects according to the truth standard respectively.
Time Frame	Participants were followed until they had coronary angiography or up to 6 months post dose to collect clinical information on cardiac events if no coronary angiography were performed

Outcome Measure Data

Analysis Population Description

Analysis population for coronary artery disease (CAD) included all subjects who received Lumason, had overall diagnostic conclusion of CAD available at peak stress for both UE-DSE and CE-DSE and had a definite truth standard diagnosis (Positive, Negative) for CAD (coronary angiography or 6 months collection of cardiac events follow-up data).

Arm/Group Title	CE-DSE - UE-DSE
Arm/Group Description	Difference between contrast-enhanced dobutamine stress echo (CE-DSE) and unenhanced dobutamine stress echo (UE-DSE) (CE-DSE - UE-DSE)
Measure Participants	170
Sensitivity	8.0 4.6%
Specificity	33.7 19.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CE-DSE - UE-DSE
	Comments	Sensitivity: superiority test comparing CE-DSE and UE-DSE based on the difference
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0896
	Comments
	Method	McNemar
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CE-DSE - UE-DSE
	Comments	Specificity: superiority test comparing CE-DSE and UE-DSE based on the difference
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	McNemar
	Comments

2. Primary Outcome

Title	Reader-Specific Percentages of Participants Identified as Having a Critical Shift From Suboptimal to Optimal Echocardiographic Images
Description	The percentage of subjects with suboptimal images (defined as >= 2 adjacent segments with inadequate left ventricular endocardial border delineation (LV EBD) in any of the 3 apical views) at unenhanced stress echo converted to adequate (reduction of suboptimal segments in any of the 3 apical views) at contrast-enhanced stress echo
Time Frame	Participants were followed until they had coronary angiography or up to 6 months post dose to collect clinical information on cardiac events if no coronary angiography was performed

Outcome Measure Data

Analysis Population Description

The analysis population for EBD included all subjects who received Lumason and had EBD data available at peak stress for both UE-DSE and CE-DSE.

Arm/Group Title	Reader 1	Reader 2	Reader 3
Arm/Group Description	Reader 1 CE-DSE	Reader 2 CE-DSE	Reader 3 CE-DSE
Measure Participants	167	167	167
Number (95% Confidence Interval) [percentage of participants]	84.4 48.8%	93.7 NaN	78.8 NaN

3. Secondary Outcome

Title	Change in Total LV EBD
Description	Measured as the change in the total LV EBD score based on the 17 segments, from peak stress unenhanced vs. peak stress contrast-enhanced. Total LV EBD score ranges from 0 to 34 and higher score is better outcome.
Time Frame	Participants were followed until they had coronary angiography or up to 6 months post dose to collect clinical information on cardiac events if no coronary angiography was performed

Outcome Measure Data

Analysis Population Description

The analysis population for EBD included all subjects who received Lumason and had EBD data available at peak stress for both UE-DSE and CE-DSE.

Arm/Group Title	UE-DSE	CE-DSE	Difference
Arm/Group Description	Unenhanced DSE	Contrast-enhanced DSE	(CE-DSE - UE-DSE)
Measure Participants	167	167	167
Reader 1	17.5 (10.83)	28.1 (8.32)	10.6 (11.98)
Reader 2	13.4 (8.57)	30.5 (4.81)	17.1 (7.87)
Reader 3	17.8 (7.04)	23.6 (7.47)	5.8 (9.17)

4. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	To obtain safety data in subjects administered Lumason during echocardiography
Time Frame	up to 72 hours post dose

Outcome Measure Data

Analysis Population Description

Safety analysis population includes all subjects who received Lumason

Arm/Group Title	Lumason
Arm/Group Description	All patients were administered, Lumason (sulphur hexafluoride lipid-type A microspheres) an ultrasound contrast agent as a single 0.03 mL/kg bolus injection during echocardiography
Measure Participants	173
Number of subjects with adverse events (AE)	21 12.1%
Number of subjects with AEs by intensity - Mild	15 8.7%
Number of subjects with AEs by intensity -Moderate	5 2.9%
Number of subjects with AEs by intensity - Severe	1 0.6%
Number of subjects with serious AEs	3 1.7%

Adverse Events

Time Frame	All adverse events (AE) that occurred from the time the subject signed the Informed Consent Form (ICF) until 72 hours after the last administration of Lumason or until the subject underwent cardiac intervention, whichever came first, were listed [recorded], [with predose AEs flagged in the subject data listings.]
Arm/Group Title	Lumason
Arm/Group Description	Lumason (sulfur hexafluoride lipid-type A microspheres) 2 mL IV injection Lumason: Lumason (sulfur hexafluoride-type A microspheres) an ultrasound contrast agent was administered as 2 single 2-mL IV injections during rest and stress echocardiography
All Cause Mortality
	Lumason
	Affected / at Risk (%)	# Events
Total	0/173 (0%)
Serious Adverse Events
	Lumason
	Affected / at Risk (%)	# Events
Total	3/173 (1.7%)
Cardiac disorders
acute myocardial infarction	1/173 (0.6%)	1
Respiratory, thoracic and mediastinal disorders
chronic obstructive pulmonary disease	1/173 (0.6%)	1
Vascular disorders
phlebitis	1/173 (0.6%)	1
Other (Not Including Serious) Adverse Events
	Lumason
	Affected / at Risk (%)	# Events
Total	21/173 (12.1%)
Cardiac disorders
Bifascicular block	1/173 (0.6%)	1
Bradycardia	1/173 (0.6%)	1
Ventricular extrasystoles	1/173 (0.6%)	1
Ventricular tachycardia	1/173 (0.6%)	1
Gastrointestinal disorders
Abdominal pain lower	1/173 (0.6%)	1
Mouth ulceration	1/173 (0.6%)	1
Nausea	1/173 (0.6%)	1
Vomiting	1/173 (0.6%)	1
General disorders
Chest discomfort	1/173 (0.6%)	1
Chest pain	1/173 (0.6%)	1
Infections and infestations
Bronchitis	1/173 (0.6%)	1
Gastrointestinal infection	2/173 (1.2%)	2
Nasopharyngitis	2/173 (1.2%)	2
Upper respiratory tract infection	1/173 (0.6%)	1
Investigations
Blood glucose increased	1/173 (0.6%)	1
Electrocardiogram change	1/173 (0.6%)	1
Haematocrit increased	1/173 (0.6%)	1
Troponin increased	1/173 (0.6%)	1
Musculoskeletal and connective tissue disorders
Pain in extremity	1/173 (0.6%)	1
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain	1/173 (0.6%)	1
Vascular disorders
Hypotension	1/173 (0.6%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.