Brain Disease
Conditions
Keywords
confirmed brain disease, highly suspected brain disease
Brief summary
This study aims at a comparison between MultiHance at a dose of 0.1 mmol/kg and 0.05 mmol/kg and Dotarem at a dose of 0.1 mmol/kg in brain tumor patients to show superiority of MultiHance.
Detailed description
This crossover study aims at a comparison between 0.1 mmol/kg MultiHance and 0.1 mmol/kg Dotarem, between 0.05 MultiHance and 0.1 mmol/kg Dotarem in terms of diagnostic preference at CE-MRI in brain tumor patients to show superiority of MultiHance.
Interventions
DRUGMultiHance 0.1 mmol/kg
MultiHance administered at 0.1 mmol/kg
DRUGDotarem
Dotarem administered at 0.1 mmol/kg
DRUGMultiHance 0.05 mmol/kg
MultiHance administered at 0.05 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 at least 18 years of age or older * Are able to give written informed consent and are willing to comply with the protocol requirements * Are scheduled to undergo MRI * Are willing to undergo two MRI procedures within 14 days * Have confirmed or are highly suspected to have brain tumor(s) (primary or secondary), as determined by: * Clinical/neurological symptomatology; * Diagnostic testing, such as CT or previous MRI examinations; or * Have had recent 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) * 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 Glomerular Filtration Rate (GFR)/estimated GFR \< 45 mL/min * Have been previously entered into this study * Have received or are scheduled for one of the following: * Surgical or chemotherapeutic treatment 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 * Have 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 post-dose follow-up examinations
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 159 patients who had post-dose exams for both MultiHance, 0.1 mmol/kg and 0.05 mmol/kg doses, and Dotarem 0.1 mmol/kg. Readers assessed whether images with MultiHance were preferred or images with Dotarem were preferred, or whether images after both exams were considered equal. An image set deemed technically inadequate by a blinded reader was excluded from efficacy analysis for that specific reader. Therefore, the number of participant exams evaluated by each reader differed slightly across readers and endpoints. |
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 159 patients who had post-dose exams for both MultiHance, 0.1 mmol/kg and 0.05 mmol/kg doses, and Dotarem 0.1 mmol/kg. Readers assessed whether images with MultiHance were preferred or images with Dotarem were preferred, or whether images after both exams were considered equal. An image set deemed technically inadequate by a blinded reader was excluded from efficacy analysis for that specific reader. Therefore, the number of participant exams evaluated by each reader differed slightly across readers and endpoints. |
| Extent of Disease | Comparison of image sets obtained within 2 to 14 days | Assessed by 3 blinded readers for each of the 159 patients who had post-dose exams for both MultiHance, 0.1 mmol/kg and 0.05 mmol/kg doses, and Dotarem 0.1 mmol/kg. Readers assessed whether images with MultiHance were preferred or images with Dotarem were preferred, or whether images after both exams were considered equal. An image set deemed technically inadequate by a blinded reader was excluded from efficacy analysis for that specific reader. Therefore, the number of participant exams evaluated by each reader differed slightly across readers and endpoints. |
| Lesion Border Delineation | Comparison of image sets obtained within 2 to 14 days | Assessed by 3 blinded readers for each of the 159 patients who had post-dose exams for both MultiHance, 0.1 mmol/kg and 0.05 mmol/kg doses, and Dotarem 0.1 mmol/kg. Readers assessed whether images with MultiHance were preferred or images with Dotarem were preferred, or whether images after both exams were considered equal. An image set deemed technically inadequate by a blinded reader was excluded from efficacy analysis for that specific reader. Therefore, the number of participant exams evaluated by each reader differed slightly across readers and endpoints. |
| Lesion to Background Ratio on Post T1-weighed Spin Echo Images | 5-10 minutes Postdose | The Unit of Measure is lesion-to-background ratio based on lesions assessed. For each lesion, Lesion-to-background ratio (LBR) = SI of lesion/SI of brain. Firstly, LBR of each lesion was assessed for each contrast agent postdose image separately, then the difference in LBR between MultiHance and Dotarem was calculated. The number presented in the result table below is the mean difference in LBR postdose (MultiHance - Dotarem) |
| Lesion-brain Contrast-to-noise Ratio | 5-10 minutes Postdose | The Unit of Measure is contrast-to-noise ratio based on lesions assessed. For each lesion, Lesion-brain Contrast-to-noise Ratio (CNR) = \[(SI of lesion - SI of brain)/SD for SI of noise\] on Postdose Images of each lesion was calculated for each contrast agent image separately, then the difference in CNR between MultiHance and Dotarem was calculated. The number presented in the result table below is the mean difference in CNR (MultiHance - Dotarem) |
| Lesion Contrast Enhancement | Comparison of image sets obtained within 2 to 14 days | Assessed by 3 blinded readers for each of the 159 patients who had post-dose exams for both MultiHance, 0.1 mmol/kg and 0.05 mmol/kg doses, and Dotarem 0.1 mmol/kg. Readers assessed whether images with MultiHance were preferred or images with Dotarem were preferred, or whether images after both exams were considered equal. An image set deemed technically inadequate by a blinded reader was excluded from efficacy analysis for that specific reader. Therefore, the number of participant exams evaluated by each reader differed slightly across readers and endpoints. |
Countries
United States
Participant flow
Recruitment details
A total of 179 patients were recruited from February 2014 through February 2015 at 14 clinical trial sites. Off-site assessment of the images was performed between 19 February - 17 March 2015 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
179 patients were enrolled and signed informed consent. Each enrolled patient was randomized and 177 were dosed with at least one contrast agent.
Participants by arm
| Arm | Count |
|---|---|
| MultiHance 0.1 mmol/kg Then Dotarem 0.1 mmol/kg Patients randomized to receive MultiHance 0.1 mmol/kg first | 31 |
| Dotarem 0.1 mmol/kg Then MultiHance 0.1 mmol/kg Patients randomized to receive Dotarem 0.1 mmol/kg first | 32 |
| MultiHance 0.05 mmol/kg Then Dotarem 0.1 mmol/kg Patients randomized to receive MultiHance 0.05 mmol/kg first | 50 |
| Dotarem 0.1 mmol/kg Then MultiHance 0.05 mmol/kg Patients randomized to receive Dotarem 0.1 mmol/kg first | 46 |
| Total | 159 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Second Injection | Image sets missing or technically inadeq | 0 | 1 | 0 | 0 |
| Second Injection | Protocol Violation | 0 | 1 | 1 | 5 |
| Washout (no Second Injection/MRI) | Withdrawal by Subject | 0 | 5 | 2 | 3 |
Baseline characteristics
| Characteristic | Dotarem 0.1 mmol/kg Then MultiHance 0.1 mmol/kg | MultiHance 0.05 mmol/kg Then Dotarem 0.1 mmol/kg | Dotarem 0.1 mmol/kg Then MultiHance 0.05 mmol/kg | MultiHance 0.1 mmol/kg Then Dotarem 0.1 mmol/kg | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 12 Participants | 14 Participants | 18 Participants | 7 Participants | 51 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants | 36 Participants | 28 Participants | 24 Participants | 108 Participants |
| Gender Female | 20 Participants | 25 Participants | 22 Participants | 20 Participants | 87 Participants |
| Gender Male | 12 Participants | 25 Participants | 24 Participants | 11 Participants | 72 Participants |
| Race/Ethnicity, Customized Asian | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Black | 1 participants | 2 participants | 0 participants | 0 participants | 3 participants |
| Race/Ethnicity, Customized Other | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 31 participants | 46 participants | 46 participants | 31 participants | 154 participants |
| Region of Enrollment Europe | 17 participants | 29 participants | 25 participants | 19 participants | 90 participants |
| Region of Enrollment United States | 15 participants | 21 participants | 21 participants | 12 participants | 69 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 65 | 2 / 70 | 3 / 104 | 7 / 105 |
| serious Total, serious adverse events | 0 / 65 | 0 / 70 | 0 / 104 | 0 / 105 |
Outcome results
Primary
Global Diagnostic Preference Between the Two Exams
Assessed by 3 blinded readers for each of the 159 patients who had post-dose exams for both MultiHance, 0.1 mmol/kg and 0.05 mmol/kg doses, and Dotarem 0.1 mmol/kg. Readers assessed whether images with MultiHance were preferred or images with Dotarem were preferred, or whether images after both exams were considered equal. An image set deemed technically inadequate by a blinded reader was excluded from efficacy analysis for that specific reader. Therefore, the number of participant exams evaluated by each reader differed slightly across readers and endpoints.
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) |
|---|---|---|---|
| MultiHance 0.1 mmol/kg Arm (Reader 1) | Global Diagnostic Preference Between the Two Exams | Contrast Agents Equal | 31 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 1) | Global Diagnostic Preference Between the Two Exams | MultiHance Preferred | 31 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 1) | Global Diagnostic Preference Between the Two Exams | Dotarem Preferred | 1 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 2) | Global Diagnostic Preference Between the Two Exams | Contrast Agents Equal | 9 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 2) | Global Diagnostic Preference Between the Two Exams | MultiHance Preferred | 51 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 2) | Global Diagnostic Preference Between the Two Exams | Dotarem Preferred | 2 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 3) | Global Diagnostic Preference Between the Two Exams | Contrast Agents Equal | 17 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 3) | Global Diagnostic Preference Between the Two Exams | MultiHance Preferred | 43 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 3) | Global Diagnostic Preference Between the Two Exams | Dotarem Preferred | 2 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 1) | Global Diagnostic Preference Between the Two Exams | Dotarem Preferred | 7 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 1) | Global Diagnostic Preference Between the Two Exams | MultiHance Preferred | 14 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 1) | Global Diagnostic Preference Between the Two Exams | Contrast Agents Equal | 75 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 2) | Global Diagnostic Preference Between the Two Exams | MultiHance Preferred | 18 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 2) | Global Diagnostic Preference Between the Two Exams | Contrast Agents Equal | 56 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 2) | Global Diagnostic Preference Between the Two Exams | Dotarem Preferred | 20 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 3) | Global Diagnostic Preference Between the Two Exams | Contrast Agents Equal | 63 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 3) | Global Diagnostic Preference Between the Two Exams | MultiHance Preferred | 15 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 3) | Global Diagnostic Preference Between the Two Exams | Dotarem Preferred | 17 participant exams |
Comparison: Null hypotheses:~A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of global diagnostic preference in an off-site pre-dose plus postdose paired global assessment.p-value: <0.000195% CI: [34.5, 60.7]Wilcoxon signed-rank test.
Comparison: Null hypotheses:~A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of global diagnostic preference in an off-site pre-dose plus post-dose paired global assessment.p-value: 0.129595% CI: [-2, 16.5]Wilcoxon signed-rank test.
Comparison: Null hypotheses:~A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of global diagnostic preference in an off-site pre-dose plus postdose paired global assessmentp-value: <0.000195% CI: [67.1, 91]Wilcoxon signed rank test
Comparison: Null hypotheses:~A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of global diagnostic preference in an off-site pre-dose plus post-dose paired global assessment.p-value: 0.750395% CI: [-15, 10.7]Wilcoxon signed rank test
Comparison: Null hypotheses:~A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of global diagnostic preference in an off-site pre-dose plus post-dose paired global assessmentp-value: <0.000195% CI: [52.8, 79.5]Wilcoxon signed rank test
Comparison: Null hypotheses:~A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of global diagnostic preference in an off-site pre-dose plus post-dose paired global assessment.p-value: 0.729795% CI: [-13.8, 9.6]Wilcoxon signed rank test
Secondary
Extent of Disease
Assessed by 3 blinded readers for each of the 159 patients who had post-dose exams for both MultiHance, 0.1 mmol/kg and 0.05 mmol/kg doses, and Dotarem 0.1 mmol/kg. Readers assessed whether images with MultiHance were preferred or images with Dotarem were preferred, or whether images after both exams were considered equal. An image set deemed technically inadequate by a blinded reader was excluded from efficacy analysis for that specific reader. Therefore, the number of participant exams evaluated by each reader differed slightly across readers and endpoints.
Time frame: Comparison of image sets obtained within 2 to 14 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MultiHance 0.1 mmol/kg Arm (Reader 1) | Extent of Disease | No Difference between MultiHance and Dotarem | 48 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 1) | Extent of Disease | MultiHance Better | 15 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 1) | Extent of Disease | Dotarem Better | 0 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 2) | Extent of Disease | No Difference between MultiHance and Dotarem | 43 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 2) | Extent of Disease | MultiHance Better | 18 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 2) | Extent of Disease | Dotarem Better | 1 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 3) | Extent of Disease | No Difference between MultiHance and Dotarem | 45 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 3) | Extent of Disease | MultiHance Better | 15 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 3) | Extent of Disease | Dotarem Better | 2 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 1) | Extent of Disease | MultiHance Better | 6 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 1) | Extent of Disease | No Difference between MultiHance and Dotarem | 84 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 1) | Extent of Disease | Dotarem Better | 6 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 2) | Extent of Disease | No Difference between MultiHance and Dotarem | 83 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 2) | Extent of Disease | MultiHance Better | 5 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 2) | Extent of Disease | Dotarem Better | 6 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 3) | Extent of Disease | MultiHance Better | 7 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 3) | Extent of Disease | Dotarem Better | 8 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 3) | Extent of Disease | No Difference between MultiHance and Dotarem | 80 participant exams |
Comparison: Null hypotheses:~A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Extent of Disease in an off-site pre-dose plus postdose paired global assessment.p-value: <0.0001Wilcoxon signed-rank test
Comparison: Null hypotheses:~A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Extent of Disease in an off-site pre-dose plus post-dose paired global assessment.p-value: 1Wilcoxon signed-rank test
Comparison: Null hypotheses:~A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Extent of Disease in an off-site pre-dose plus postdose paired global assessment.p-value: <0.0001Wilcoxon signed-rank test
Comparison: Null hypotheses:~A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Extent of Disease in an off-site pre-dose plus postdose paired global assessment.p-value: 1Wilcoxon signed-rank test
Comparison: Null hypotheses:~A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Extent of Disease in an off-site pre-dose plus postdose paired global assessment.p-value: 0.0023Wilcoxon signed-rank test
Comparison: Null hypotheses:~A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Extent of Disease in an off-site pre-dose plus postdose paired global assessment.p-value: 1Wilcoxon signed-rank test
Secondary
Lesion Border Delineation
Assessed by 3 blinded readers for each of the 159 patients who had post-dose exams for both MultiHance, 0.1 mmol/kg and 0.05 mmol/kg doses, and Dotarem 0.1 mmol/kg. Readers assessed whether images with MultiHance were preferred or images with Dotarem were preferred, or whether images after both exams were considered equal. An image set deemed technically inadequate by a blinded reader was excluded from efficacy analysis for that specific reader. Therefore, the number of participant exams evaluated by each reader differed slightly across readers and endpoints.
Time frame: Comparison of image sets obtained within 2 to 14 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MultiHance 0.1 mmol/kg Arm (Reader 1) | Lesion Border Delineation | Contrast Agents Equal | 33 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 1) | Lesion Border Delineation | MultiHance Preferred | 29 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 1) | Lesion Border Delineation | Dotarem Preferred | 1 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 2) | Lesion Border Delineation | Contrast Agents Equal | 27 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 2) | Lesion Border Delineation | MultiHance Preferred | 34 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 2) | Lesion Border Delineation | Dotarem Preferred | 1 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 3) | Lesion Border Delineation | Contrast Agents Equal | 35 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 3) | Lesion Border Delineation | MultiHance Preferred | 25 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 3) | Lesion Border Delineation | Dotarem Preferred | 2 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 1) | Lesion Border Delineation | MultiHance Preferred | 11 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 1) | Lesion Border Delineation | Contrast Agents Equal | 76 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 1) | Lesion Border Delineation | Dotarem Preferred | 9 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 2) | Lesion Border Delineation | MultiHance Preferred | 12 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 2) | Lesion Border Delineation | Contrast Agents Equal | 66 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 2) | Lesion Border Delineation | Dotarem Preferred | 16 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 3) | Lesion Border Delineation | Contrast Agents Equal | 77 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 3) | Lesion Border Delineation | MultiHance Preferred | 8 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 3) | Lesion Border Delineation | Dotarem Preferred | 10 participant exams |
Comparison: This is a secondary analysis.~Null hypotheses:~A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Border Delineation in an off-site pre-dose plus postdose paired global assessment.p-value: <0.0001Wilcoxon signed-rank test
Comparison: This is a secondary analysis.~Null hypotheses:~A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Border Delineation in an off-site pre-dose plus post-dose paired global assessment.p-value: 0.8238Wilcoxon signed-rank test
Comparison: This is a secondary analysis.~Null hypotheses:~A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Border Delineation in an off-site pre-dose plus postdose paired global assessment.p-value: <0.0001Wilcoxon signed rank test
Comparison: This is a secondary analysis.~Null hypotheses:~A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Border Delineation in an off-site pre-dose plus postdose paired global assessment.p-value: 0.4597Wilcoxon signed rank test
Comparison: This is a secondary analysis.~Null hypotheses:~A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Border Delineation in an off-site pre-dose plus postdose paired global assessment.p-value: <0.0001Wilcoxon signed rank test
Comparison: This is a secondary analysis.~Null hypotheses:~A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Border Delineation in an off-site pre-dose plus postdose paired global assessment.p-value: 0.8145Wilcoxon signed rank test
Secondary
Lesion-brain Contrast-to-noise Ratio
The Unit of Measure is contrast-to-noise ratio based on lesions assessed. For each lesion, Lesion-brain Contrast-to-noise Ratio (CNR) = \[(SI of lesion - SI of brain)/SD for SI of noise\] on Postdose Images of each lesion was calculated for each contrast agent image separately, then the difference in CNR between MultiHance and Dotarem was calculated. The number presented in the result table below is the mean difference in CNR (MultiHance - Dotarem)
Time frame: 5-10 minutes Postdose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MultiHance 0.1 mmol/kg Arm (Reader 1) | Lesion-brain Contrast-to-noise Ratio | 17.40 ratio based on lesions assessed | Standard Deviation 36.14 |
| MultiHance 0.1 mmol/kg Arm (Reader 2) | Lesion-brain Contrast-to-noise Ratio | 31.82 ratio based on lesions assessed | Standard Deviation 45.28 |
| MultiHance 0.1 mmol/kg Arm (Reader 3) | Lesion-brain Contrast-to-noise Ratio | 39.73 ratio based on lesions assessed | Standard Deviation 65.26 |
| MultiHance 0.05 mmol/kg Arm (Reader 1) | Lesion-brain Contrast-to-noise Ratio | 15.72 ratio based on lesions assessed | Standard Deviation 36.05 |
| MultiHance 0.05 mmol/kg Arm (Reader 2) | Lesion-brain Contrast-to-noise Ratio | 19.06 ratio based on lesions assessed | Standard Deviation 29.37 |
| MultiHance 0.05 mmol/kg Arm (Reader 3) | Lesion-brain Contrast-to-noise Ratio | 23.03 ratio based on lesions assessed | Standard Deviation 49.53 |
p-value: 0.0002Mixed Models Analysis
p-value: <0.0001Mixed Models Analysis
p-value: <0.0001Mixed Models Analysis
p-value: <0.0001Mixed Models Analysis
p-value: <0.0001Mixed Models Analysis
p-value: 0.0003Mixed Models Analysis
Secondary
Lesion Contrast Enhancement
Assessed by 3 blinded readers for each of the 159 patients who had post-dose exams for both MultiHance, 0.1 mmol/kg and 0.05 mmol/kg doses, and Dotarem 0.1 mmol/kg. Readers assessed whether images with MultiHance were preferred or images with Dotarem were preferred, or whether images after both exams were considered equal. An image set deemed technically inadequate by a blinded reader was excluded from efficacy analysis for that specific reader. Therefore, the number of participant exams evaluated by each reader differed slightly across readers and endpoints.
Time frame: Comparison of image sets obtained within 2 to 14 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MultiHance 0.1 mmol/kg Arm (Reader 1) | Lesion Contrast Enhancement | No Difference between MultiHance and Dotarem | 31 Participant Exams |
| MultiHance 0.1 mmol/kg Arm (Reader 1) | Lesion Contrast Enhancement | Dotarem Better | 1 Participant Exams |
| MultiHance 0.1 mmol/kg Arm (Reader 1) | Lesion Contrast Enhancement | MultiHance Better | 31 Participant Exams |
| MultiHance 0.1 mmol/kg Arm (Reader 2) | Lesion Contrast Enhancement | MultiHance Better | 51 Participant Exams |
| MultiHance 0.1 mmol/kg Arm (Reader 2) | Lesion Contrast Enhancement | Dotarem Better | 2 Participant Exams |
| MultiHance 0.1 mmol/kg Arm (Reader 2) | Lesion Contrast Enhancement | No Difference between MultiHance and Dotarem | 9 Participant Exams |
| MultiHance 0.1 mmol/kg Arm (Reader 3) | Lesion Contrast Enhancement | Dotarem Better | 2 Participant Exams |
| MultiHance 0.1 mmol/kg Arm (Reader 3) | Lesion Contrast Enhancement | MultiHance Better | 43 Participant Exams |
| MultiHance 0.1 mmol/kg Arm (Reader 3) | Lesion Contrast Enhancement | No Difference between MultiHance and Dotarem | 17 Participant Exams |
| MultiHance 0.05 mmol/kg Arm (Reader 1) | Lesion Contrast Enhancement | MultiHance Better | 10 Participant Exams |
| MultiHance 0.05 mmol/kg Arm (Reader 1) | Lesion Contrast Enhancement | No Difference between MultiHance and Dotarem | 77 Participant Exams |
| MultiHance 0.05 mmol/kg Arm (Reader 1) | Lesion Contrast Enhancement | Dotarem Better | 9 Participant Exams |
| MultiHance 0.05 mmol/kg Arm (Reader 2) | Lesion Contrast Enhancement | No Difference between MultiHance and Dotarem | 56 Participant Exams |
| MultiHance 0.05 mmol/kg Arm (Reader 2) | Lesion Contrast Enhancement | Dotarem Better | 20 Participant Exams |
| MultiHance 0.05 mmol/kg Arm (Reader 2) | Lesion Contrast Enhancement | MultiHance Better | 18 Participant Exams |
| MultiHance 0.05 mmol/kg Arm (Reader 3) | Lesion Contrast Enhancement | Dotarem Better | 17 Participant Exams |
| MultiHance 0.05 mmol/kg Arm (Reader 3) | Lesion Contrast Enhancement | MultiHance Better | 14 Participant Exams |
| MultiHance 0.05 mmol/kg Arm (Reader 3) | Lesion Contrast Enhancement | No Difference between MultiHance and Dotarem | 64 Participant Exams |
Comparison: Null hypotheses:~A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Contrast Enhancement in an off-site pre-dose plus postdose paired global assessment.p-value: <0.0001Wilcoxon signed-rank test
Comparison: Null hypotheses:~A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Contrast Enhancement in an off-site pre-dose plus post-dose paired global assessment.p-value: 1Wilcoxon signed-rank test
Comparison: Null hypotheses:~A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Contrast Enhancement in an off-site pre-dose plus postdose paired global assessment.p-value: <0.0001Wilcoxon signed-rank test
Comparison: Null hypotheses:~A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Contrast Enhancement in an off-site pre-dose plus postdose paired global assessment.p-value: 0.7503Wilcoxon signed-rank test
Comparison: Null hypotheses:~A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Contrast Enhancement in an off-site pre-dose plus postdose paired global assessment.p-value: <0.0001Wilcoxon signed-rank test
Comparison: Null hypotheses:~A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.05 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Contrast Enhancement in an off-site pre-dose plus postdose paired global assessment.p-value: 0.5983Wilcoxon signed-rank test
Secondary
Lesion Internal Morphology
Assessed by 3 blinded readers for each of the 159 patients who had post-dose exams for both MultiHance, 0.1 mmol/kg and 0.05 mmol/kg doses, and Dotarem 0.1 mmol/kg. Readers assessed whether images with MultiHance were preferred or images with Dotarem were preferred, or whether images after both exams were considered equal. An image set deemed technically inadequate by a blinded reader was excluded from efficacy analysis for that specific reader. Therefore, the number of participant exams evaluated by each reader differed slightly across readers and endpoints.
Time frame: Comparison of image sets obtained within 2 to 14 days
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MultiHance 0.1 mmol/kg Arm (Reader 1) | Lesion Internal Morphology | No Difference Between MultiHance and Dotarem | 53 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 1) | Lesion Internal Morphology | MultiHance better | 10 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 1) | Lesion Internal Morphology | Dotarem better | 0 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 2) | Lesion Internal Morphology | No Difference Between MultiHance and Dotarem | 48 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 2) | Lesion Internal Morphology | MultiHance better | 14 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 2) | Lesion Internal Morphology | Dotarem better | 0 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 3) | Lesion Internal Morphology | No Difference Between MultiHance and Dotarem | 38 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 3) | Lesion Internal Morphology | MultiHance better | 23 participant exams |
| MultiHance 0.1 mmol/kg Arm (Reader 3) | Lesion Internal Morphology | Dotarem better | 1 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 1) | Lesion Internal Morphology | No Difference Between MultiHance and Dotarem | 88 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 1) | Lesion Internal Morphology | MultiHance better | 4 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 1) | Lesion Internal Morphology | Dotarem better | 4 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 2) | Lesion Internal Morphology | No Difference Between MultiHance and Dotarem | 87 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 2) | Lesion Internal Morphology | MultiHance better | 3 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 2) | Lesion Internal Morphology | Dotarem better | 4 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 3) | Lesion Internal Morphology | MultiHance better | 5 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 3) | Lesion Internal Morphology | Dotarem better | 8 participant exams |
| MultiHance 0.05 mmol/kg Arm (Reader 3) | Lesion Internal Morphology | No Difference Between MultiHance and Dotarem | 82 participant exams |
Comparison: Null hypotheses:~A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Internal Morphology in an off-site pre-dose plus postdose paired global assessment.p-value: 0.002Wilcoxon signed-rank test
Comparison: Null hypotheses:~A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Internal Morphology in an off-site pre-dose plus post-dose paired global assessment.p-value: 1Wilcoxon signed-rank test
Comparison: Null hypotheses:~A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Internal Morphology in an off-site pre-dose plus postdose paired global assessment.p-value: 0.0001Wilcoxon signed-rank test
Comparison: Null hypotheses:~A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Internal Morphology in an off-site pre-dose plus postdose paired global assessment.p-value: 1Wilcoxon signed-rank test
Comparison: Null hypotheses:~A 0.1 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Internal Morphology in an off-site pre-dose plus postdose paired global assessment.p-value: <0.0001Wilcoxon signed-rank test
Comparison: Null hypotheses:~A 0.05 mmol/kg dose of MULTIHANCE is equal to a 0.1 mmol/kg dose of DOTAREM, in terms of the assessment of Lesion Internal Morphology in an off-site pre-dose plus postdose paired global assessment.p-value: 0.5811Wilcoxon signed-rank test
Secondary
Lesion to Background Ratio on Post T1-weighed Spin Echo Images
The Unit of Measure is lesion-to-background ratio based on lesions assessed. For each lesion, Lesion-to-background ratio (LBR) = SI of lesion/SI of brain. Firstly, LBR of each lesion was assessed for each contrast agent postdose image separately, then the difference in LBR between MultiHance and Dotarem was calculated. The number presented in the result table below is the mean difference in LBR postdose (MultiHance - Dotarem)
Time frame: 5-10 minutes Postdose
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MultiHance 0.1 mmol/kg Arm (Reader 1) | Lesion to Background Ratio on Post T1-weighed Spin Echo Images | 0.22 ratio based on lesions assessed | Standard Deviation 0.24 |
| MultiHance 0.1 mmol/kg Arm (Reader 2) | Lesion to Background Ratio on Post T1-weighed Spin Echo Images | 0.24 ratio based on lesions assessed | Standard Deviation 0.2 |
| MultiHance 0.1 mmol/kg Arm (Reader 3) | Lesion to Background Ratio on Post T1-weighed Spin Echo Images | 0.21 ratio based on lesions assessed | Standard Deviation 0.23 |
| MultiHance 0.05 mmol/kg Arm (Reader 1) | Lesion to Background Ratio on Post T1-weighed Spin Echo Images | -0.01 ratio based on lesions assessed | Standard Deviation 0.21 |
| MultiHance 0.05 mmol/kg Arm (Reader 2) | Lesion to Background Ratio on Post T1-weighed Spin Echo Images | 0.03 ratio based on lesions assessed | Standard Deviation 0.15 |
| MultiHance 0.05 mmol/kg Arm (Reader 3) | Lesion to Background Ratio on Post T1-weighed Spin Echo Images | 0.01 ratio based on lesions assessed | Standard Deviation 0.15 |
p-value: <0.0001Mixed Models Analysis
p-value: 0.6898Mixed Models Analysis
p-value: <0.0001Mixed Models Analysis
p-value: 0.1156Mixed Models Analysis
p-value: <0.0001Mixed Models Analysis
p-value: 0.7726Mixed Models Analysis