Brain Disease
Conditions
Keywords
Have confirmed or are highly suspected of brain disease
Brief summary
This study aims at a direct comparison between ProHance (0.1 mmol/kg) and a validated comparator Gadovist/Gadavist (0.1 mmol/kg) in a crossover intra-individual design in subjects with brain tumors to confirm the identical overall technical and diagnostic performance of the two MR contrast agents.
Detailed description
Adult patients were given two MRI exams, one after injection of ProHance (0.1 mmol/kg) and one after injection of Gadovist/Gadavist (0.1 mmol/kg). The exams were performed with identical equipment and imaging parameters with the order of the two exams randomized and 2-14 days between the first and the second MRI exam. Image data was evaluated by 3 expert neuroradiologist blinded to the agent administered and patient clinical data.
Interventions
DRUGgadoteridol
ProHance 0.1 mmol/kg
DRUGgadobutrol
Gadovist/Gadavist 0.1 mmol/kg
Sponsors
Bracco Diagnostics, Inc
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
DIAGNOSTIC
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Are scheduled to undergo MRI * Are willing to undergo two MRI procedures within 14 days * Have confirmed or are highly suspected of brain disease likely to enhance as determined by the following: * Clinical/neurological symptomatology; * Diagnostic testing, such as CT or previous MRI examinations; or * Have had previous brain surgery and are to be evaluated for recurrence.
Exclusion criteria
* Are pregnant or lactating females. Exclude the possibility of pregnancy: * by testing on site at the institution within 24 hours prior to the start of each investigational product administration; or * by history (i.e., tubal ligation or hysterectomy); or * post menopausal with a minimum of 1 year without menses * Have any known allergy to one or more of the ingredients in the investigational products, or have a history of hypersensitivity to any metals * Have congestive heart failure (class IV according to the classification of the New York Heart Association; see Appendix A) * Have suffered a stroke within a year * Have received or are scheduled to receive any other contrast medium in the 24 hours preceding through the 24 hours following Exam 1, and in the 24 hours preceding through the 24 hours following Exam 2 * Have received or are scheduled to receive an investigational compound and/or medical device within 30 days before admission into the present study, through the 24 hours post-administration of the second investigational product. * Have moderate-to-severe renal impairment, defined as a GFR/eGFR \< 45 mL/min. * Have been previously entered into this study * Have received or are scheduled for one of the following: * Surgery within three weeks prior to the first examination or between the two examinations * Initiation of steroid therapy between the two examinations * Radiosurgery between the two examinations * Have any contraindications to MRI such as a pace-maker, magnetic material (i.e., surgical clips) or any other conditions that would preclude proximity to a strong magnetic field. * Are suffering from severe claustrophobia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Global Diagnostic Preference Between the Two Exams | Comparison of image sets obtained within 2 to 14 days | Assessed by 3 blinded readers for each of the 198 patients who had post-dose exams for both ProHance and Gadovist/Gadavist. Readers assessed whether images with ProHance were preferred or images with Gadovist/Gadavist were preferred, or whether images after both exams were considered equal. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Lesion Internal Morphology | Comparison of image sets obtained within 2 to 14 days | Assessed by 3 blinded readers for each of the 198 patients who had post-dose exams for both ProHance and Gadovist/Gadavist. Readers assessed whether images with ProHance were preferred or images with Gadovist/Gadavist were preferred, or whether images after both exams were considered equal. |
| Extent of Disease | Comparison of image sets obtained within 2 to 14 days | Assessed by 3 blinded readers for each of the 198 patients who had post-dose exams for both ProHance and Gadovist/Gadavist. Readers assessed whether images with ProHance were preferred or images with Gadovist/Gadavist were preferred, or whether images after both exams were considered equal. |
| Lesion Contrast Enhancement | Comparison of image sets obtained within 2 to 14 days | Assessed by 3 blinded readers for each of the 198 patients who had post-dose exams for both ProHance and Gadovist/Gadavist. Readers assessed whether images with ProHance were preferred or images with Gadovist/Gadavist were preferred, or whether images after both exams were considered equal. |
| Lesion Border Delineation | Comparison of image sets obtained within 2 to 14 days | Assessed by 3 blinded readers for each of the 198 patients who had post-dose exams for both ProHance and Gadovist/Gadavist. Readers assessed whether images with ProHance were preferred or images with Gadovist/Gadavist were preferred, or whether images after both exams were considered equal. |
| Percentage Signal Intensity Enhancement on Postdose Images | 5-10 minutes Postdose | Mean difference in percentage signal intensity enhancement on postdose T1-weighted SE/FSE images (ProHance - Gadovist/Gadavist) |
| Lesion Detection | 5-10 minutes Postdose | Lesion detection rate by contrast agent and reader |
| Accuracy for Tumor Characterization | 5-10 minutes Postdose | Blinded reader assessment of accuracy of tumor characterization (benign/malignant) - patient level assessment |
| Lesion to Background Ratio on Post T1-weighed Spin Echo Images | 5-10 minutes Postdose | Mean of difference in signal intensity postdose (ProHance - Gadovist/Gadavist) |
Countries
United States
Participant flow
Recruitment details
A total of 229 patients were recruited from September 2012 through November 2013 at 19 clinical trial sites. Off-site assessment of the images was performed between 21 January and 3 April 2014 by 3 board-certified neuroradiologists blinded as to which contrast agent was used, patient clinical information, and the results of other imaging studies.
Pre-assignment details
229 patients were enrolled and signed informed consent. Each enrolled patient was randomized and dosed with at least one contrast agent.
Participants by arm
| Arm | Count |
|---|---|
| ProHance Then Gadovist/Gadavist Per Protocol=patients who completed both exams, had global paired image data available, and had no major protocol violations | 93 |
| Gadovist/Gadavist Then ProHance Per Protocol=patients who completed both exams, had global paired image data available, and had no major protocol violations | 105 |
| Total | 198 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Washout (no Second Injection/MRI) | Withdrawal by Subject | 13 | 7 |
Baseline characteristics
| Characteristic | ProHance Then Gadovist/Gadavist | Gadovist/Gadavist Then ProHance | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 23 Participants | 35 Participants | 58 Participants |
| Age, Categorical Between 18 and 65 years | 70 Participants | 70 Participants | 140 Participants |
| Age, Continuous | 54.5 years STANDARD_DEVIATION 14.27 | 55.9 years STANDARD_DEVIATION 14.29 | 55.2 years STANDARD_DEVIATION 14.31 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 88 Participants | 102 Participants | 190 Participants |
| Region of Enrollment Canada | 8 participants | 8 participants | 16 participants |
| Region of Enrollment Europe | 39 participants | 51 participants | 90 participants |
| Region of Enrollment United States | 46 participants | 46 participants | 92 participants |
| Sex: Female, Male Female | 50 Participants | 58 Participants | 108 Participants |
| Sex: Female, Male Male | 43 Participants | 47 Participants | 90 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 222 | 8 / 216 |
| serious Total, serious adverse events | 0 / 222 | 0 / 216 |
Outcome results
Primary
Global Diagnostic Preference Between the Two Exams
Assessed by 3 blinded readers for each of the 198 patients who had post-dose exams for both ProHance and Gadovist/Gadavist. Readers assessed whether images with ProHance were preferred or images with Gadovist/Gadavist were preferred, or whether images after both exams were considered equal.
Time frame: Comparison of image sets obtained within 2 to 14 days
Population: Per Protocol=patients who completed both exams, had global paired image data available, and had no major protocol violations
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Reader 1 | Global Diagnostic Preference Between the Two Exams | Contrast Agents Equal | 171 participant exams |
| Reader 1 | Global Diagnostic Preference Between the Two Exams | ProHance Preferred | 14 participant exams |
| Reader 1 | Global Diagnostic Preference Between the Two Exams | Gadovist/Gadavist Preferred | 13 participant exams |
| Reader 2 | Global Diagnostic Preference Between the Two Exams | Contrast Agents Equal | 180 participant exams |
| Reader 2 | Global Diagnostic Preference Between the Two Exams | ProHance Preferred | 7 participant exams |
| Reader 2 | Global Diagnostic Preference Between the Two Exams | Gadovist/Gadavist Preferred | 7 participant exams |
| Reader 3 | Global Diagnostic Preference Between the Two Exams | ProHance Preferred | 1 participant exams |
| Reader 3 | Global Diagnostic Preference Between the Two Exams | Gadovist/Gadavist Preferred | 0 participant exams |
| Reader 3 | Global Diagnostic Preference Between the Two Exams | Contrast Agents Equal | 195 participant exams |
p-value: 0.851695% CI: [-4.6, 5.6]Wilcoxon (Mann-Whitney)
p-value: 195% CI: [-3.8, 3.8]Wilcoxon (Mann-Whitney)
p-value: 195% CI: [-0.5, 1.5]Wilcoxon (Mann-Whitney)
Secondary
Accuracy for Tumor Characterization
Blinded reader assessment of accuracy of tumor characterization (benign/malignant) - patient level assessment
Time frame: 5-10 minutes Postdose
Population: Subjects with histologically confirmed lesions
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Reader 1 | Accuracy for Tumor Characterization | Patients with Tumors Correctly Categorized | 94 participants |
| Reader 1 | Accuracy for Tumor Characterization | Patients with Tumors Incorrectly Categorized | 34 participants |
| Reader 2 | Accuracy for Tumor Characterization | Patients with Tumors Correctly Categorized | 96 participants |
| Reader 2 | Accuracy for Tumor Characterization | Patients with Tumors Incorrectly Categorized | 32 participants |
| Reader 3 | Accuracy for Tumor Characterization | Patients with Tumors Correctly Categorized | 106 participants |
| Reader 3 | Accuracy for Tumor Characterization | Patients with Tumors Incorrectly Categorized | 22 participants |
| Reader 2 - Gadovist/Gadavist | Accuracy for Tumor Characterization | Patients with Tumors Correctly Categorized | 101 participants |
| Reader 2 - Gadovist/Gadavist | Accuracy for Tumor Characterization | Patients with Tumors Incorrectly Categorized | 27 participants |
| Reader 3 - ProHance | Accuracy for Tumor Characterization | Patients with Tumors Correctly Categorized | 93 participants |
| Reader 3 - ProHance | Accuracy for Tumor Characterization | Patients with Tumors Incorrectly Categorized | 35 participants |
| Reader 3 - Gadovist/Gadavist | Accuracy for Tumor Characterization | Patients with Tumors Correctly Categorized | 83 participants |
| Reader 3 - Gadovist/Gadavist | Accuracy for Tumor Characterization | Patients with Tumors Incorrectly Categorized | 45 participants |
Comparison: McNemar test of difference (ProHance minus Gadovist/Gadavist) in accuracy for tumor characterizationp-value: 0.6949McNemar
Comparison: McNemar test of difference (ProHance minus Gadovist/Gadavist) in accuracy for tumor characterizationp-value: 0.1317McNemar
Comparison: McNemar test of difference (ProHance minus Gadovist/Gadavist) in accuracy for tumor characterizationp-value: 0.0124McNemar
Secondary
Extent of Disease
Assessed by 3 blinded readers for each of the 198 patients who had post-dose exams for both ProHance and Gadovist/Gadavist. Readers assessed whether images with ProHance were preferred or images with Gadovist/Gadavist were preferred, or whether images after both exams were considered equal.
Time frame: Comparison of image sets obtained within 2 to 14 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Reader 1 | Extent of Disease | No Difference between ProHance and Gadovist/Gadavi | 196 participant exams |
| Reader 1 | Extent of Disease | ProHance Better | 1 participant exams |
| Reader 1 | Extent of Disease | Gadovist/Gadavist Better | 1 participant exams |
| Reader 2 | Extent of Disease | No Difference between ProHance and Gadovist/Gadavi | 190 participant exams |
| Reader 2 | Extent of Disease | ProHance Better | 2 participant exams |
| Reader 2 | Extent of Disease | Gadovist/Gadavist Better | 2 participant exams |
| Reader 3 | Extent of Disease | ProHance Better | 1 participant exams |
| Reader 3 | Extent of Disease | Gadovist/Gadavist Better | 0 participant exams |
| Reader 3 | Extent of Disease | No Difference between ProHance and Gadovist/Gadavi | 195 participant exams |
p-value: 1Wilcoxon (Mann-Whitney)
p-value: 1Wilcoxon (Mann-Whitney)
p-value: 1Wilcoxon (Mann-Whitney)
Secondary
Lesion Border Delineation
Assessed by 3 blinded readers for each of the 198 patients who had post-dose exams for both ProHance and Gadovist/Gadavist. Readers assessed whether images with ProHance were preferred or images with Gadovist/Gadavist were preferred, or whether images after both exams were considered equal.
Time frame: Comparison of image sets obtained within 2 to 14 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Reader 1 | Lesion Border Delineation | No Difference between Prohance and Gadovist/Gadavi | 181 participant exams |
| Reader 1 | Lesion Border Delineation | ProHance Better | 8 participant exams |
| Reader 1 | Lesion Border Delineation | Gadovist/Gadavist Better | 9 participant exams |
| Reader 2 | Lesion Border Delineation | No Difference between Prohance and Gadovist/Gadavi | 189 participant exams |
| Reader 2 | Lesion Border Delineation | ProHance Better | 2 participant exams |
| Reader 2 | Lesion Border Delineation | Gadovist/Gadavist Better | 3 participant exams |
| Reader 3 | Lesion Border Delineation | ProHance Better | 1 participant exams |
| Reader 3 | Lesion Border Delineation | Gadovist/Gadavist Better | 0 participant exams |
| Reader 3 | Lesion Border Delineation | No Difference between Prohance and Gadovist/Gadavi | 195 participant exams |
p-value: 1Wilcoxon (Mann-Whitney)
p-value: 1Wilcoxon (Mann-Whitney)
p-value: 1Wilcoxon (Mann-Whitney)
Secondary
Lesion Contrast Enhancement
Assessed by 3 blinded readers for each of the 198 patients who had post-dose exams for both ProHance and Gadovist/Gadavist. Readers assessed whether images with ProHance were preferred or images with Gadovist/Gadavist were preferred, or whether images after both exams were considered equal.
Time frame: Comparison of image sets obtained within 2 to 14 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Reader 1 | Lesion Contrast Enhancement | Gadovist/Gadavist Better | 14 participant exams |
| Reader 1 | Lesion Contrast Enhancement | No Difference between ProHance and Gadovist/Gadavi | 170 participant exams |
| Reader 1 | Lesion Contrast Enhancement | ProHance Better | 14 participant exams |
| Reader 2 | Lesion Contrast Enhancement | Gadovist/Gadavist Better | 10 participant exams |
| Reader 2 | Lesion Contrast Enhancement | ProHance Better | 10 participant exams |
| Reader 2 | Lesion Contrast Enhancement | No Difference between ProHance and Gadovist/Gadavi | 174 participant exams |
| Reader 3 | Lesion Contrast Enhancement | No Difference between ProHance and Gadovist/Gadavi | 193 participant exams |
| Reader 3 | Lesion Contrast Enhancement | ProHance Better | 2 participant exams |
| Reader 3 | Lesion Contrast Enhancement | Gadovist/Gadavist Better | 1 participant exams |
p-value: 1Wilcoxon (Mann-Whitney)
p-value: 1Wilcoxon (Mann-Whitney)
p-value: 1Wilcoxon (Mann-Whitney)
Secondary
Lesion Detection
Lesion detection rate by contrast agent and reader
Time frame: 5-10 minutes Postdose
Population: Per protocol patients with histologically confirmed lesions
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Reader 1 | Lesion Detection | True Positive (Patients) | 133 participant exams |
| Reader 1 | Lesion Detection | False Negative (Pa | 6 participant exams |
| Reader 2 | Lesion Detection | True Positive (Patients) | 135 participant exams |
| Reader 2 | Lesion Detection | False Negative (Pa | 4 participant exams |
| Reader 3 | Lesion Detection | True Positive (Patients) | 137 participant exams |
| Reader 3 | Lesion Detection | False Negative (Pa | 2 participant exams |
| Reader 2 - Gadovist/Gadavist | Lesion Detection | True Positive (Patients) | 136 participant exams |
| Reader 2 - Gadovist/Gadavist | Lesion Detection | False Negative (Pa | 3 participant exams |
| Reader 3 - ProHance | Lesion Detection | True Positive (Patients) | 136 participant exams |
| Reader 3 - ProHance | Lesion Detection | False Negative (Pa | 3 participant exams |
| Reader 3 - Gadovist/Gadavist | Lesion Detection | True Positive (Patients) | 132 participant exams |
| Reader 3 - Gadovist/Gadavist | Lesion Detection | False Negative (Pa | 7 participant exams |
p-value: 0.3173McNemar
p-value: 0.5637McNemar
p-value: 0.0455McNemar
Secondary
Lesion Internal Morphology
Assessed by 3 blinded readers for each of the 198 patients who had post-dose exams for both ProHance and Gadovist/Gadavist. Readers assessed whether images with ProHance were preferred or images with Gadovist/Gadavist were preferred, or whether images after both exams were considered equal.
Time frame: Comparison of image sets obtained within 2 to 14 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Reader 1 | Lesion Internal Morphology | No Difference Between ProHance and Gadovist/Gadavi | 195 participant exams |
| Reader 1 | Lesion Internal Morphology | ProHance better | 2 participant exams |
| Reader 1 | Lesion Internal Morphology | Gadovist/Gadavist betterB | 1 participant exams |
| Reader 2 | Lesion Internal Morphology | No Difference Between ProHance and Gadovist/Gadavi | 188 participant exams |
| Reader 2 | Lesion Internal Morphology | ProHance better | 2 participant exams |
| Reader 2 | Lesion Internal Morphology | Gadovist/Gadavist betterB | 4 participant exams |
| Reader 3 | Lesion Internal Morphology | ProHance better | 1 participant exams |
| Reader 3 | Lesion Internal Morphology | Gadovist/Gadavist betterB | 0 participant exams |
| Reader 3 | Lesion Internal Morphology | No Difference Between ProHance and Gadovist/Gadavi | 195 participant exams |
p-value: 1Wilcoxon (Mann-Whitney)
p-value: 0.6875Wilcoxon (Mann-Whitney)
p-value: 1Wilcoxon (Mann-Whitney)
Secondary
Lesion to Background Ratio on Post T1-weighed Spin Echo Images
Mean of difference in signal intensity postdose (ProHance - Gadovist/Gadavist)
Time frame: 5-10 minutes Postdose
Population: Per-protocol population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Reader 1 | Lesion to Background Ratio on Post T1-weighed Spin Echo Images | -0.02 signal intensity | Standard Deviation 0.17 |
| Reader 2 | Lesion to Background Ratio on Post T1-weighed Spin Echo Images | -0.16 signal intensity | Standard Deviation 1.12 |
| Reader 3 | Lesion to Background Ratio on Post T1-weighed Spin Echo Images | -0.01 signal intensity | Standard Deviation 0.18 |
p-value: 0.2758Mixed Models Analysis
p-value: 0.0676Mixed Models Analysis
p-value: 0.5267Mixed Models Analysis
Secondary
Percentage Signal Intensity Enhancement on Postdose Images
Mean difference in percentage signal intensity enhancement on postdose T1-weighted SE/FSE images (ProHance - Gadovist/Gadavist)
Time frame: 5-10 minutes Postdose
Population: Per-protocol population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Reader 1 | Percentage Signal Intensity Enhancement on Postdose Images | 1.06 percentage signal intensity enhancement | Standard Deviation 28.61 |
| Reader 2 | Percentage Signal Intensity Enhancement on Postdose Images | -2.09 percentage signal intensity enhancement | Standard Deviation 29.06 |
| Reader 3 | Percentage Signal Intensity Enhancement on Postdose Images | -1.59 percentage signal intensity enhancement | Standard Deviation 29.16 |
p-value: 0.6201Mixed Models Analysis
p-value: 0.4514Mixed Models Analysis
p-value: 0.7722Mixed Models Analysis