Clinical Trial Results:
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
Summary
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EudraCT number |
2015-001962-25 |
Trial protocol |
GB BE |
Global end of trial date |
25 Feb 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
30 Jun 2021
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First version publication date |
30 Jun 2021
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
BR1-142
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02552238 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Bracco Imaging S.p.A
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Sponsor organisation address |
Via Folli 50, Milan, Italy, 20134
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Public contact |
GM & RA Clinical Research, Bracco Suisse SA, 41 228848803, patricia.caillon@bracco.com
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Scientific contact |
GM & RA Clinical Research, Bracco Suisse SA, 41 228848803, patricia.caillon@bracco.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
30 May 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
22 Jun 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
25 Feb 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
Primary Objectives:
To assess the efficacy of SonoVue®-enhanced dobutamine stress echocardiography (DSE) in subjects with suspected or known CAD having suboptimal left ventricular (LV) endocardial border delineation (EBD) at unenhanced echocardiography in terms of:
- Sensitivity and specificity for the detection or exclusion of CAD in unenhanced versus SonoVue®-enhanced DSE using coronary angiography or clinical follow-up as the truth standard;
- Critical shift from suboptimal (≥2 adjacent segments inadequate on any apical view) at unenhanced dobutamine stress echocardiography (UE-DSE) to adequate images (reduction of suboptimal adjacent segments) for LV EBD at contrast-enhanced dobutamine stress echocardiography (CE-DSE).
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Protection of trial subjects |
Investigators agreed to make no informal changes to the protocol, except when necessary to protect the safety, the rights or the welfare of subjects. In addition, the Sponsor ensures insurance coverage for damages concerning the subject during the study.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
12 Oct 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Canada: 6
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Country: Number of subjects enrolled |
United States: 119
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Country: Number of subjects enrolled |
United Kingdom: 42
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Country: Number of subjects enrolled |
Belgium: 7
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Worldwide total number of subjects |
174
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EEA total number of subjects |
7
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
103
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From 65 to 84 years |
70
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85 years and over |
1
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Recruitment
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Recruitment details |
First subject in: 12 October 2015; Last subject completed: 22 June 2017; Blinded Read Assessment Completed: 15 February 2018 | ||||||||||
Pre-assignment
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Screening details |
174 subjects signed the informed consent: 2 discontinued study participation prior to contrast administration, 172 subjects received Lumason/SonoVue and are included in the Safety Analysis Population. An additional 2 subjects discontinued study participation, post dose, due to adverse events, therefore 170 subjects completed the study. | ||||||||||
Period 1
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Period 1 title |
Overall Trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||
Arms
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Arm title
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LUMASON/SonoVue | ||||||||||
Arm description |
LUMASON/SonoVue (Sulfur hexafluoride lipid-type A microspheres/Sulphur hexafluoride microbubbles) 2-mL intravenous injection | ||||||||||
Arm type |
Experimental | ||||||||||
Investigational medicinal product name |
LUMASON/SonoVue
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Investigational medicinal product code |
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Other name |
Lumason, SonoVue
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Pharmaceutical forms |
Powder for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Ultrasound contrast agent administered as 2 single-dose 2-mL intravenous injections during rest and stress echocardiography
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Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: 174 subjects enrolled in the study; however, 2 subjects withdrew consent prior to contrast administration leaving 172 subjects who received intravenous LUMASON/SonoVue. |
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Baseline characteristics reporting groups
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Reporting group title |
Overall Trial
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Reporting group description |
Subjects who enrolled, signed informed consent and were administered investigational product. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
LUMASON/SonoVue
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Reporting group description |
LUMASON/SonoVue (Sulfur hexafluoride lipid-type A microspheres/Sulphur hexafluoride microbubbles) 2-mL intravenous injection | ||
Subject analysis set title |
Sensitivity for Detection or Exclusion of CAD
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set 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 occurrence 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 is the percentage of correctly diagnosed subjects by stress echo over the total positive subjects according to the truth standard.
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Subject analysis set title |
Specificity for Detection or Exclusion of CAD
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set 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 occurrence 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.
Specificity is the percentage of correctly diagnosed subjects by stress echo over the total negative subjects according to the truth standard.
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Subject analysis set title |
Critical Shift from Sub- to Optimal Echocardiographic Images
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
Reader-Specific Percentages of Participants Identified as having a Critical Shift from Suboptimal to Optimal Echocardiographic Images
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.
Analysis population for EBD included all subjects who received Lumason/SonoVue and had EBD data available at peak stress for both UE-DSE and CE-DSE.
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Subject analysis set title |
Total LV EBD (Unenhanced)
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
Analysis population for EBD included all subjects who received Lumason/SonoVue and had EBD data available at peak stress for both UE-DSE and CE-DSE.
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Subject analysis set title |
Total LV EBD (Contrast-enhanced)
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
Analysis population for EBD included all subjects who received Lumason/SonoVue and had EBD data available at peak stress for both UE-DSE and CE-DSE.
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Subject analysis set title |
Change in Total LV EBD (Difference [CE-DSE - UE-DSE])
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
Analysis population for EBD included all subjects who received Lumason/SonoVue and had EBD data available at peak stress for both UE-DSE and CE-DSE.
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Subject analysis set title |
Dummy set
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
EudraCT does not allow single arm/group statistical analysis. Due to the limitations with the EudraCT system, a Dummy set was created and used as a comparison group. This dummy set is a work-around to that limitation. No subjects in this set (N=0).
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End point title |
Sensitivity for Detection or Exclusion of Coronary Artery Disease (CAD) | ||||||||||||
End point description |
Analysis population for coronary artery disease (CAD) included all subjects who received Lumason/SonoVue, had overall diagnostic conclusion of CAD available at peak stress for both unenhanced dobutamine stress echocardiography (UE-DSE) and contrast-enhanced dobutamine stress echocardiography (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).
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End point type |
Primary
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End point timeframe |
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.
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Notes [1] - Due to limitations with the EudraCT system, a Dummy set was created as a comparison group. N=0. |
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Statistical analysis title |
Difference between CE-DSE and UE-DSE | ||||||||||||
Statistical analysis description |
Analysis population for coronary artery disease (CAD) included all subjects who received LUMASON/SonoVue, had overall diagnostic conclusion of CAD available at peak stress for both unenhanced dobutamine stress echocardiography (UE-DSE) and contrast-enhanced dobutamine stress echocardiography (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).
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Comparison groups |
Sensitivity for Detection or Exclusion of CAD v Dummy set
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Number of subjects included in analysis |
82
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Analysis specification |
Pre-specified
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Analysis type |
superiority [2] | ||||||||||||
P-value |
= 0.0067 | ||||||||||||
Method |
Mcnemar | ||||||||||||
Confidence interval |
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Notes [2] - Difference between contrast-enhanced dobutamine stress echocardiography (CE-DSE) and unenhanced dobutamine stress echocardiography (UE-DSE) (CE-DSE - UE-DSE) EudraCT does not allow single arm/group statistical analysis. Due to the limitations with the EudraCT system, a Dummy set was created and used as a comparison group. This dummy set is a work-around to that limitation. No subjects in this set. Therefore, N=81. |
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End point title |
Specificity for Detection or Exclusion of Coronary Artery Disease (CAD) | ||||||||||||
End point description |
Analysis population for coronary artery disease (CAD) included all subjects who received Lumason/SonoVue, had overall diagnostic conclusion of CAD available at peak stress for both unenhanced dobutamine stress echocardiography (UE-DSE) and contrast-enhanced dobutamine stress echocardiography (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).
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End point type |
Primary
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End point timeframe |
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.
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Notes [3] - Due to limitations with the EudraCT system, a Dummy set was created as a comparison group. N=0. |
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Statistical analysis title |
Difference between CE-DSE and UE-DSE | ||||||||||||
Statistical analysis description |
Analysis population for coronary artery disease (CAD) included all subjects who received Lumason/SonoVue, had overall diagnostic conclusion of CAD available at peak stress for both unenhanced dobutamine stress echocardiography (UE-DSE) and contrast-enhanced dobutamine stress echocardiography (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).
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Comparison groups |
Specificity for Detection or Exclusion of CAD v Dummy set
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Number of subjects included in analysis |
88
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Analysis specification |
Pre-specified
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Analysis type |
superiority [4] | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Mcnemar | ||||||||||||
Confidence interval |
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Notes [4] - Difference between contrast-enhanced dobutamine stress echocardiography (CE-DSE) and unenhanced dobutamine stress echocardiography (UE-DSE) (CE-DSE - UE-DSE) EudraCT does not allow single arm/group statistical analysis. Due to the limitations with the EudraCT system, a Dummy set was created and used as a comparison group. This dummy set is a work-around to that limitation. No subjects in this set. Therefore, N=87. |
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End point title |
Critical Shift from Suboptimal to Optimal Echocardiographic Images [5] | ||||||||||||||
End point 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 dobutamine stress echocardiography (CE-DSE).
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End point type |
Primary
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End point timeframe |
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.
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Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was performed for this end point. |
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No statistical analyses for this end point |
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End point title |
Change in Total LV EBD | ||||||||||||||||||||||||||||
End point 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.
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End point type |
Secondary
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End point timeframe |
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.
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No statistical analyses for this end point |
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End point title |
Summary of Adverse Events | ||||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
From the time of signed informed consent up to 72 hours post dose.
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
All adverse events (AEs) that occurred from the time the subject signed Informed Consent until 72 hours after the last administration of LUMASON/SonoVue or until the subject underwent cardiac intervention, whichever came first, were recorded.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18.1
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Reporting groups
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Reporting group title |
LUMASON/SonoVue Safety Population
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Reporting group description |
All adverse events (AEs) that occurred from the time the subject signed Informed Consent until 72 hours after the last administration of LUMASON/SonoVue or until the subject underwent cardiac intervention, whichever came first, were recorded. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |