Coronary Artery Disease
Conditions
Keywords
iodinated contrast media, coronary artery disease
Brief summary
The purpose of this study is to demonstrate the (statistical) non-inferiority of iobitridol (Xenetix® 350) when compared to contrast agents with higher iodine concentrations, iopromide (Ultravist® 370) and iomeprol (Iomeron® 400) in terms of coronary CT scan evaluability (quality and interpretability of images).
Detailed description
Patients suspected of coronary artery disease were submitted to coronary CT angiography using either iobitridol or contrast agents with higher iodine concentrations (iopromide or iomeprol). Independent off-site readers evaluated image quality regarding the ability to identify coronary artery stenosis (score 0- non evaluable to 4- excellent quality). The study was aimed at showing the non-inferiority of iobitridol in its ability to provide evaluable CT scans for the identification of coronary stenosis.
Interventions
Sponsors
Guerbet
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female adult patient (having reached legal majority age) * Symptomatic patient suspected for coronary artery disease scheduled for a coronary CT angiography
Exclusion criteria
* Patient with a heart rate \> 65 beats per minute (bpm) and contraindication or intolerance to b-blocker administration * Patient with arrhythmia or non-sinus rhythm * Patient with decompensated heart failure * Patient with evidence of ongoing or active clinical instability (suspected or known acute myocardial infarction, cardiac shock, acute pulmonary oedema) * Patient who has previously undergone coronary artery bypass graft * Patient who has previously undergone percutaneous transluminal coronary stent placement * Patient with artificial heart valve * Patient with known moderate to severe aortic stenosis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate of Patients With Evaluable CT Scans i.e. Allowing Identification of Coronary Artery Stenosis According to Off-site Reading Assessment | < 24h | Evaluability was based upon the off-site assessment of 18-coronary segments graded for image quality with a 5-point scale.4= Excellent quality, fully confidence without any doubts concerning the presence/absence of luminal stenosis; 3= Good quality, confidence concerning the presence/absence of luminal stenosis; 2= Moderate quality, relative confidence, with minor doubts concerning the presence/absence of luminal stenosis; 1= Poor quality, some doubts concerning the presence/absence of stenosis; 0= Non diagnostic. A patient's CT scan was considered as evaluable for identification of coronary artery stenosis if none of the 18 coronary segments had a score of 0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average Image Quality According to Off-site Reading | <24h | For each patient, all 18 coronary segments were graded for image quality using a 5-point evaluation scale (from 0=non-diagnostic to 4=excellent). The average image quality was evaluated using the off-site readings, by averaging the scores obtained for the 18 segments used to determine the CT evaluability (primary criteria). |
| Coronary Track Rate | <24h | A post processing software automatically tracked the number of distal segments of the left anterior descending coronary artery, the left circumflex coronary artery and the right coronary artery . The number of segments tracked per patient were assessed by an independent off-site radiologist. |
| Average Signal Attenuation After IV Injection of Contrast | <1h | Attenuation of signal was measured off-site on post-injection images of four coronary segments, in the ascending aorta and in the left ventricle, then it was averaged at the patient level. |
| Average Signal-to-Noise Ratio (Average SNR) | <1h | Signal attenuation was measured by off-site radiologists in the lumen of 4 coronary segments, in the ascending aorta and in the left ventricle and was expressed in Hounsfield Unit (HU). Measurements were set in post-injection images for the 6 territories. A measure of noise in CT scans was collected at least in the aorta and if possible in the muscle and/or air. Signal-to-Noise Ratios (SNR) of post-injection images were derived in all territories from attenuation measurements according to the following formula: SNR Territory = Post Attenuation / Image Noise |
| Average Contrast-to-noise Ratio (Average CNR) | <1h | Signal attenuation was measured by off-site radiologists in the lumen of 4 coronary segments in the ascending aorta and the in left ventricle and expressed in Hounsfield Unit (HU). A measure of noise in CT scans was collected at least in the aorta and if possible in the muscle and/or air. In territories where pre and post signal attenuation measures were both available, the contrast-to-noise ratio was computed according to the following formula: CNR = (Post Att - Baseline Att) / Image Noise |
Countries
France, Germany, Italy, Spain, Switzerland
Participant flow
Recruitment details
A total of 468 patients from 5 European countries were enrolled and evaluated between 3 November 2010 and 17 September 2012.
Participants by arm
| Arm | Count |
|---|---|
| Iobitridol Patients were IV injected with a single dose of iobitridol before a coronary CT angiography | 155 |
| Iopromide Patients were IV injected with a single dose of iopromide before a coronary CT angiography | 160 |
| Iomeprol Patients were IV injected with a single dose of iomeprol before a coronary CT angiography | 153 |
| Total | 468 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 1 |
| Overall Study | asymptomatic patient | 1 | 0 | 0 |
| Overall Study | beta-blocker contraindicated | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Iobitridol | Iopromide | Iomeprol | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 51 Participants | 59 Participants | 45 Participants | 155 Participants |
| Age, Categorical Between 18 and 65 years | 104 Participants | 101 Participants | 108 Participants | 313 Participants |
| Age, Continuous | 57.9 years STANDARD_DEVIATION 12.2 | 58.7 years STANDARD_DEVIATION 11.6 | 56.9 years STANDARD_DEVIATION 13.4 | 57.8 years STANDARD_DEVIATION 12.4 |
| Region of Enrollment France | 59 participants | 61 participants | 59 participants | 179 participants |
| Region of Enrollment Germany | 41 participants | 45 participants | 41 participants | 127 participants |
| Region of Enrollment Italy | 25 participants | 24 participants | 23 participants | 72 participants |
| Region of Enrollment Spain | 21 participants | 21 participants | 20 participants | 62 participants |
| Region of Enrollment Switzerland | 9 participants | 9 participants | 10 participants | 28 participants |
| Sex: Female, Male Female | 65 Participants | 68 Participants | 65 Participants | 198 Participants |
| Sex: Female, Male Male | 90 Participants | 92 Participants | 88 Participants | 270 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 23 / 152 | 31 / 159 | 23 / 152 |
| serious Total, serious adverse events | 0 / 152 | 0 / 159 | 1 / 152 |
Outcome results
Primary
Rate of Patients With Evaluable CT Scans i.e. Allowing Identification of Coronary Artery Stenosis According to Off-site Reading Assessment
Evaluability was based upon the off-site assessment of 18-coronary segments graded for image quality with a 5-point scale.4= Excellent quality, fully confidence without any doubts concerning the presence/absence of luminal stenosis; 3= Good quality, confidence concerning the presence/absence of luminal stenosis; 2= Moderate quality, relative confidence, with minor doubts concerning the presence/absence of luminal stenosis; 1= Poor quality, some doubts concerning the presence/absence of stenosis; 0= Non diagnostic. A patient's CT scan was considered as evaluable for identification of coronary artery stenosis if none of the 18 coronary segments had a score of 0.
Time frame: < 24h
Population: Full Analysis Set: all patients who underwent the coronary CT scan examination and had available assessments of the primary endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Iobitridol | Rate of Patients With Evaluable CT Scans i.e. Allowing Identification of Coronary Artery Stenosis According to Off-site Reading Assessment | 92.1 Percentage of patients | Standard Error 2.2 |
| Iopromide | Rate of Patients With Evaluable CT Scans i.e. Allowing Identification of Coronary Artery Stenosis According to Off-site Reading Assessment | 95.4 Percentage of patients | Standard Error 1.7 |
| Iomeprol | Rate of Patients With Evaluable CT Scans i.e. Allowing Identification of Coronary Artery Stenosis According to Off-site Reading Assessment | 94.6 Percentage of patients | Standard Error 1.8 |
Comparison: Iobitridol was compared to the best of the two comparators. The two-sided 95% confidence interval (CI) of the difference between both proportions (Iobitridol - Comparator) was computed and the lower limit of the CI compared to the clinical non-inferiority limit in the study. The non-inferiority of iobitridol over the best comparator was established if the lower limit of the two-sided 95% CI was equal to or higher than the clinical non-inferiority limit.p-value: 0.0595% CI: [-0.088, 0.021]Chi-squared
Secondary
Average Contrast-to-noise Ratio (Average CNR)
Signal attenuation was measured by off-site radiologists in the lumen of 4 coronary segments in the ascending aorta and the in left ventricle and expressed in Hounsfield Unit (HU). A measure of noise in CT scans was collected at least in the aorta and if possible in the muscle and/or air. In territories where pre and post signal attenuation measures were both available, the contrast-to-noise ratio was computed according to the following formula: CNR = (Post Att - Baseline Att) / Image Noise
Time frame: <1h
Population: Full Analysis Set: included all patients who underwent the examination and had available assessments of the primary endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Iobitridol | Average Contrast-to-noise Ratio (Average CNR) | 14.4 Hounsfield Units:Hounsfield Units | Standard Deviation 5.4 |
| Iopromide | Average Contrast-to-noise Ratio (Average CNR) | 15.3 Hounsfield Units:Hounsfield Units | Standard Deviation 4.8 |
| Iomeprol | Average Contrast-to-noise Ratio (Average CNR) | 15.8 Hounsfield Units:Hounsfield Units | Standard Deviation 6.5 |
p-value: 0.09Fisher Exact
Secondary
Average Image Quality According to Off-site Reading
For each patient, all 18 coronary segments were graded for image quality using a 5-point evaluation scale (from 0=non-diagnostic to 4=excellent). The average image quality was evaluated using the off-site readings, by averaging the scores obtained for the 18 segments used to determine the CT evaluability (primary criteria).
Time frame: <24h
Population: Full Analysis Set: all patients who underwent the coronary CT scan examination and had available assessments of the primary endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Iobitridol | Average Image Quality According to Off-site Reading | 3.5 Image quality Score on a scale | Standard Deviation 0.9 |
| Iopromide | Average Image Quality According to Off-site Reading | 3.5 Image quality Score on a scale | Standard Deviation 0.8 |
| Iomeprol | Average Image Quality According to Off-site Reading | 3.4 Image quality Score on a scale | Standard Deviation 0.9 |
p-value: 0.75Fisher Exact
Secondary
Average Signal Attenuation After IV Injection of Contrast
Attenuation of signal was measured off-site on post-injection images of four coronary segments, in the ascending aorta and in the left ventricle, then it was averaged at the patient level.
Time frame: <1h
Population: Full Analysis Set: all patients who underwent the coronary CT scan examination and had available assessments of the primary endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Iobitridol | Average Signal Attenuation After IV Injection of Contrast | 426.3 Hounsfield Units | Standard Deviation 92.9 |
| Iopromide | Average Signal Attenuation After IV Injection of Contrast | 449.8 Hounsfield Units | Standard Deviation 88.1 |
| Iomeprol | Average Signal Attenuation After IV Injection of Contrast | 466.4 Hounsfield Units | Standard Deviation 104.6 |
p-value: 0.001Fisher Exact
Secondary
Average Signal-to-Noise Ratio (Average SNR)
Signal attenuation was measured by off-site radiologists in the lumen of 4 coronary segments, in the ascending aorta and in the left ventricle and was expressed in Hounsfield Unit (HU). Measurements were set in post-injection images for the 6 territories. A measure of noise in CT scans was collected at least in the aorta and if possible in the muscle and/or air. Signal-to-Noise Ratios (SNR) of post-injection images were derived in all territories from attenuation measurements according to the following formula: SNR Territory = Post Attenuation / Image Noise
Time frame: <1h
Population: Full Analysis Set: included all patients who underwent the examination and had available assessments of the primary endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Iobitridol | Average Signal-to-Noise Ratio (Average SNR) | 16.2 Hounsfield Units:Hounsfield Units | Standard Deviation 5.6 |
| Iopromide | Average Signal-to-Noise Ratio (Average SNR) | 17.1 Hounsfield Units:Hounsfield Units | Standard Deviation 5 |
| Iomeprol | Average Signal-to-Noise Ratio (Average SNR) | 17.6 Hounsfield Units:Hounsfield Units | Standard Deviation 6.6 |
p-value: 0.109Fisher Exact
Secondary
Coronary Track Rate
A post processing software automatically tracked the number of distal segments of the left anterior descending coronary artery, the left circumflex coronary artery and the right coronary artery . The number of segments tracked per patient were assessed by an independent off-site radiologist.
Time frame: <24h
Population: Full Analysis Set population: all patients who underwent the coronary CT scan examination and had available assessments of the primary endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Iobitridol | Coronary Track Rate | 10.9 Number of tracked segments per patient | Standard Deviation 2.2 |
| Iopromide | Coronary Track Rate | 10.8 Number of tracked segments per patient | Standard Deviation 2.4 |
| Iomeprol | Coronary Track Rate | 11.1 Number of tracked segments per patient | Standard Deviation 2.3 |