Central Nervous System Diseases, Diagnostic Self Evaluation
Conditions
Keywords
CNS, Contrast Agent, MRI, Dotarem, Magnevist
Brief summary
The purpose of this study is to look at the safety (what are the side effects)and efficacy (how well does it work) of Dotarem® when used in taking images of the brain / spine. The results will be compared to the results of MRI taken without Dotarem.
Detailed description
This is a study involving the use of Magnetic Resonance Imaging (MRI) contrast agents called Dotarem®. The purpose of this study is to look at the safety (what are the side effects) and efficacy (how well does it work) of Dotarem® when used for taking images of the brain and spine. The results of the MRI will be compared to the results of images taken without Dotarem®.
Interventions
DRUGDotarem (gadoterate meglumine)
0.1 mmol/kg by body weight, single IV injection
0.1 mmol/kg by body weight, single IV injection
Sponsors
Guerbet
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adult subject and pediatric subjects (aged greater than or equal to two (2) years). * Is referred for a contrast-enhanced MRI of the CNS based on the results of a previous imaging procedure. * Female of childbearing potential patients must have effective contraception (contraceptive pill or intra-uterine device) or be surgically sterilized or post-menopausal (minimum 12 months amenorrhea), or have a documented negative urine pregnancy test within 24 hours prior to study MRI. * Has been fully informed about the study, and has consented to participate.
Exclusion criteria
* Having acute or chronic grade IV or V renal insufficiency. * Known class III/IV congestive heart failure. * Suffering from long QT syndrome. * Unstable health condition or circumstances (e.g. suffering from severe claustrophobia). * Having any contraindications to MRI such as a pace-maker, magnetic material or any other conditions that would preclude proximity to a strong magnetic field. * Known allergy to Gadolinium chelates. * Having received any contrast agent within 3 days prior to study contrast administration, or is scheduled to receive any contrast agent within 24 hours after the study contrast administration. * Pregnant, breast feeding, or planning to become pregnant during the trial. * Previously participated in this trial. * Having participated within 30 days in another clinical trial involving an investigational drug. * Any condition which, based on the investigator's clinical judgement, would prevent the patient from completing all trial assessments and visits. * Inability or unwillingness to cooperate with the requirements of this trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| MRI Lesion Visualization (Border Delineation, Internal Morphology and Contrast Enhancement) at Patient Level for Both Pre and Paired Evaluation | up to 24 hours | To demonstrate the superiority of combined unenhanced and Dotarem enhanced MRI (PAIRED) compared to unenhanced MRI (PRE) in terms of lesion visualization. Unenhanced MRI refers to MRI before administration of contrast agent. Enhanced MRI refers to MRI after contrast agent injection. Pre refers to unenhanced MRI. PAIRED refer to combined unenhanced and enhanced MRI. The measure used a specific scale with 3-point levels to assess lesion visualization. At lesion level, the scale range is from 0 through 1 to 2. Score 0 means a worse outcome and score 2 means a better outcome. Patient score is the sum of all lesion scores. Up to 5 of the largest representative lesions were assessed. At patient level, the maximum score is 10, minimum score is 0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Image Quality Score | up to 24 hours | Image quality was evaluated for each lesion according to a 3-point scale with the following grades; poor (1), fair (2) or good (3), and an overall score per patient was calculated. At patient level, the maximum score is 3, minimum score is 1. Higher scores mean a better image quality. |
| Diagnostic Confidence Score | up to 24 hours | Level of diagnostic confidence when evaluating the MRI modalities was graded using a 5-point scale as nil (1), poor (2), moderate (3), high (4) and excellent (5). |
| Number of Lesions | up to 24 hours | The number of lesions for which observations could be made was calculated for each MRI modality and results are summarized per patient |
Countries
Argentina, Austria, Brazil, Chile, France, Germany, Italy, South Korea, Spain, United Kingdom, United States
Participant flow
Recruitment details
First patient First Visit : 16 Sept 2010 Last patient Last Visit : 16 Nov 2011 Locations: radiology departments
Pre-assignment details
Any patient who did not fulfill eligibility criteria was not randomized / assigned to a treatment group.
Participants by arm
| Arm | Count |
|---|---|
| Magnevist (Gadopentetate Dimeglumine) adults received Magnevist as 1:2 ratio compared to Dotarem | 119 |
| Dotarem (Gadoterate Meglumine) adults received Dotarem as 2:1 ratio compared to Magnevist. | 245 |
| Dotarem 2 (Gadoterate Meglumine) All children were assigned to Dotarem | 38 |
| Total | 402 |
Baseline characteristics
| Characteristic | Magnevist (Gadopentetate Dimeglumine) | Dotarem (Gadoterate Meglumine) | Dotarem 2 (Gadoterate Meglumine) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 38 Participants | 38 Participants |
| Age, Categorical >=65 years | 30 Participants | 60 Participants | 0 Participants | 90 Participants |
| Age, Categorical Between 18 and 65 years | 89 Participants | 185 Participants | 0 Participants | 274 Participants |
| Age, Continuous | 55.95 years STANDARD_DEVIATION 14.43 | 53.17 years STANDARD_DEVIATION 14.35 | 9.29 years STANDARD_DEVIATION 4.49 | 49.8 years STANDARD_DEVIATION 19 |
| Region of Enrollment Argentina | 12 participants | 22 participants | 14 participants | 48 participants |
| Region of Enrollment Austria | 10 participants | 20 participants | 0 participants | 30 participants |
| Region of Enrollment Brazil | 5 participants | 8 participants | 4 participants | 17 participants |
| Region of Enrollment Chile | 3 participants | 5 participants | 3 participants | 11 participants |
| Region of Enrollment France | 13 participants | 30 participants | 0 participants | 43 participants |
| Region of Enrollment Germany | 20 participants | 40 participants | 0 participants | 60 participants |
| Region of Enrollment Italy | 7 participants | 15 participants | 0 participants | 22 participants |
| Region of Enrollment Korea, Republic of | 14 participants | 26 participants | 0 participants | 40 participants |
| Region of Enrollment Spain | 2 participants | 8 participants | 0 participants | 10 participants |
| Region of Enrollment United Kingdom | 3 participants | 6 participants | 0 participants | 9 participants |
| Region of Enrollment United States | 30 participants | 65 participants | 17 participants | 112 participants |
| Sex: Female, Male Female | 65 Participants | 131 Participants | 22 Participants | 218 Participants |
| Sex: Female, Male Male | 54 Participants | 114 Participants | 16 Participants | 184 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 240 | 0 / 117 | 0 / 38 |
| other Total, other adverse events | 12 / 240 | 9 / 117 | 8 / 38 |
| serious Total, serious adverse events | 0 / 240 | 1 / 117 | 1 / 38 |
Outcome results
Primary
MRI Lesion Visualization (Border Delineation, Internal Morphology and Contrast Enhancement) at Patient Level for Both Pre and Paired Evaluation
To demonstrate the superiority of combined unenhanced and Dotarem enhanced MRI (PAIRED) compared to unenhanced MRI (PRE) in terms of lesion visualization. Unenhanced MRI refers to MRI before administration of contrast agent. Enhanced MRI refers to MRI after contrast agent injection. Pre refers to unenhanced MRI. PAIRED refer to combined unenhanced and enhanced MRI. The measure used a specific scale with 3-point levels to assess lesion visualization. At lesion level, the scale range is from 0 through 1 to 2. Score 0 means a worse outcome and score 2 means a better outcome. Patient score is the sum of all lesion scores. Up to 5 of the largest representative lesions were assessed. At patient level, the maximum score is 10, minimum score is 0.
Time frame: up to 24 hours
Population: The primary analysis was performed at the patient level using off-site readings by 3 readers. The number of participants for analysis depended on the number of evaluable cases (PRE and PAIRED) determined by each reader. Only adult participants were included in this data set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dotarem (Gadoterate Meglumine) - PRE | MRI Lesion Visualization (Border Delineation, Internal Morphology and Contrast Enhancement) at Patient Level for Both Pre and Paired Evaluation | Border Delineation Blinded Reader 3 | 1.43 units on a scale | Standard Deviation 1.29 |
| Dotarem (Gadoterate Meglumine) - PRE | MRI Lesion Visualization (Border Delineation, Internal Morphology and Contrast Enhancement) at Patient Level for Both Pre and Paired Evaluation | Internal Morphology Blinded Reader 3 | 1.45 units on a scale | Standard Deviation 1.13 |
| Dotarem (Gadoterate Meglumine) - PRE | MRI Lesion Visualization (Border Delineation, Internal Morphology and Contrast Enhancement) at Patient Level for Both Pre and Paired Evaluation | Border Delineation Blinded Reader 2 | 1.62 units on a scale | Standard Deviation 1.43 |
| Dotarem (Gadoterate Meglumine) - PRE | MRI Lesion Visualization (Border Delineation, Internal Morphology and Contrast Enhancement) at Patient Level for Both Pre and Paired Evaluation | Contrast Enhancement Blinded Reader 1 | 0.01 units on a scale | Standard Deviation 0.2 |
| Dotarem (Gadoterate Meglumine) - PRE | MRI Lesion Visualization (Border Delineation, Internal Morphology and Contrast Enhancement) at Patient Level for Both Pre and Paired Evaluation | Internal Morphology Blinded Reader 1 | 0.97 units on a scale | Standard Deviation 1.05 |
| Dotarem (Gadoterate Meglumine) - PRE | MRI Lesion Visualization (Border Delineation, Internal Morphology and Contrast Enhancement) at Patient Level for Both Pre and Paired Evaluation | Contrast Enhancement Blinded Reader 2 | 0.01 units on a scale | Standard Deviation 0.15 |
| Dotarem (Gadoterate Meglumine) - PRE | MRI Lesion Visualization (Border Delineation, Internal Morphology and Contrast Enhancement) at Patient Level for Both Pre and Paired Evaluation | Border Delineation Blinded Reader 1 | 1.06 units on a scale | Standard Deviation 1.23 |
| Dotarem (Gadoterate Meglumine) - PRE | MRI Lesion Visualization (Border Delineation, Internal Morphology and Contrast Enhancement) at Patient Level for Both Pre and Paired Evaluation | Contrast Enhancement Blinded Reader 3 | 0.01 units on a scale | Standard Deviation 0.13 |
| Dotarem (Gadoterate Meglumine) - PRE | MRI Lesion Visualization (Border Delineation, Internal Morphology and Contrast Enhancement) at Patient Level for Both Pre and Paired Evaluation | Internal Morphology Blinded Reader 2 | 1.76 units on a scale | Standard Deviation 1.24 |
| Dotarem (Gadoterate Meglumine) - PAIRED | MRI Lesion Visualization (Border Delineation, Internal Morphology and Contrast Enhancement) at Patient Level for Both Pre and Paired Evaluation | Contrast Enhancement Blinded Reader 3 | 2.95 units on a scale | Standard Deviation 2.44 |
| Dotarem (Gadoterate Meglumine) - PAIRED | MRI Lesion Visualization (Border Delineation, Internal Morphology and Contrast Enhancement) at Patient Level for Both Pre and Paired Evaluation | Border Delineation Blinded Reader 2 | 4.49 units on a scale | Standard Deviation 2.94 |
| Dotarem (Gadoterate Meglumine) - PAIRED | MRI Lesion Visualization (Border Delineation, Internal Morphology and Contrast Enhancement) at Patient Level for Both Pre and Paired Evaluation | Border Delineation Blinded Reader 3 | 2.54 units on a scale | Standard Deviation 2.3 |
| Dotarem (Gadoterate Meglumine) - PAIRED | MRI Lesion Visualization (Border Delineation, Internal Morphology and Contrast Enhancement) at Patient Level for Both Pre and Paired Evaluation | Internal Morphology Blinded Reader 1 | 3.70 units on a scale | Standard Deviation 2.63 |
| Dotarem (Gadoterate Meglumine) - PAIRED | MRI Lesion Visualization (Border Delineation, Internal Morphology and Contrast Enhancement) at Patient Level for Both Pre and Paired Evaluation | Internal Morphology Blinded Reader 2 | 4.49 units on a scale | Standard Deviation 2.93 |
| Dotarem (Gadoterate Meglumine) - PAIRED | MRI Lesion Visualization (Border Delineation, Internal Morphology and Contrast Enhancement) at Patient Level for Both Pre and Paired Evaluation | Internal Morphology Blinded Reader 3 | 2.93 units on a scale | Standard Deviation 2.3 |
| Dotarem (Gadoterate Meglumine) - PAIRED | MRI Lesion Visualization (Border Delineation, Internal Morphology and Contrast Enhancement) at Patient Level for Both Pre and Paired Evaluation | Contrast Enhancement Blinded Reader 1 | 3.11 units on a scale | Standard Deviation 2.52 |
| Dotarem (Gadoterate Meglumine) - PAIRED | MRI Lesion Visualization (Border Delineation, Internal Morphology and Contrast Enhancement) at Patient Level for Both Pre and Paired Evaluation | Contrast Enhancement Blinded Reader 2 | 3.73 units on a scale | Standard Deviation 2.67 |
| Dotarem (Gadoterate Meglumine) - PAIRED | MRI Lesion Visualization (Border Delineation, Internal Morphology and Contrast Enhancement) at Patient Level for Both Pre and Paired Evaluation | Border Delineation Blinded Reader 1 | 3.30 units on a scale | Standard Deviation 2.64 |
p-value: <0.001Regression, Logistic
Secondary
Diagnostic Confidence Score
Level of diagnostic confidence when evaluating the MRI modalities was graded using a 5-point scale as nil (1), poor (2), moderate (3), high (4) and excellent (5).
Time frame: up to 24 hours
Population: The number of participants for analysis depended on the number of evaluable cases (PRE and PAIRED) determined by each reader. Only adult participants are included in this data set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dotarem (Gadoterate Meglumine) - PRE | Diagnostic Confidence Score | Reader 3 | 3.47 units on a scale | Standard Deviation 1.22 |
| Dotarem (Gadoterate Meglumine) - PRE | Diagnostic Confidence Score | Reader 1 | 3.04 units on a scale | Standard Deviation 0.9 |
| Dotarem (Gadoterate Meglumine) - PRE | Diagnostic Confidence Score | Reader 2 | 2.84 units on a scale | Standard Deviation 0.61 |
| Dotarem (Gadoterate Meglumine) - PAIRED | Diagnostic Confidence Score | Reader 2 | 4.89 units on a scale | Standard Deviation 0.31 |
| Dotarem (Gadoterate Meglumine) - PAIRED | Diagnostic Confidence Score | Reader 1 | 4.59 units on a scale | Standard Deviation 0.64 |
| Dotarem (Gadoterate Meglumine) - PAIRED | Diagnostic Confidence Score | Reader 3 | 4.41 units on a scale | Standard Deviation 0.98 |
| Magnevist (Gadopentetate Dimeglumine) - PRE | Diagnostic Confidence Score | Reader 3 | 3.59 units on a scale | Standard Deviation 1.29 |
| Magnevist (Gadopentetate Dimeglumine) - PRE | Diagnostic Confidence Score | Reader 1 | 3.11 units on a scale | Standard Deviation 0.86 |
| Magnevist (Gadopentetate Dimeglumine) - PRE | Diagnostic Confidence Score | Reader 2 | 2.85 units on a scale | Standard Deviation 0.59 |
| Magnevist (Gadopentetate Dimeglumine) - PAIRED | Diagnostic Confidence Score | Reader 2 | 4.92 units on a scale | Standard Deviation 0.36 |
| Magnevist (Gadopentetate Dimeglumine) - PAIRED | Diagnostic Confidence Score | Reader 1 | 4.66 units on a scale | Standard Deviation 0.64 |
| Magnevist (Gadopentetate Dimeglumine) - PAIRED | Diagnostic Confidence Score | Reader 3 | 4.59 units on a scale | Standard Deviation 0.81 |
p-value: <0.001Regression, Logistic
p-value: <0.001Regression, Logistic
Secondary
Image Quality Score
Image quality was evaluated for each lesion according to a 3-point scale with the following grades; poor (1), fair (2) or good (3), and an overall score per patient was calculated. At patient level, the maximum score is 3, minimum score is 1. Higher scores mean a better image quality.
Time frame: up to 24 hours
Population: The number of participants for analysis depended on the number of evaluable cases (PRE and PAIRED) determined by each reader. Only adult participants are included in this data set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dotarem (Gadoterate Meglumine) - PRE | Image Quality Score | Reader 1 | 1.41 units on a scale | Standard Deviation 0.52 |
| Dotarem (Gadoterate Meglumine) - PRE | Image Quality Score | Reader 3 | 2.00 units on a scale | Standard Deviation 0.07 |
| Dotarem (Gadoterate Meglumine) - PRE | Image Quality Score | Reader 2 | 1.72 units on a scale | Standard Deviation 0.45 |
| Dotarem (Gadoterate Meglumine) - PAIRED | Image Quality Score | Reader 1 | 2.98 units on a scale | Standard Deviation 0.2 |
| Dotarem (Gadoterate Meglumine) - PAIRED | Image Quality Score | Reader 3 | 2.99 units on a scale | Standard Deviation 0.11 |
| Dotarem (Gadoterate Meglumine) - PAIRED | Image Quality Score | Reader 2 | 3.00 units on a scale | Standard Deviation 0 |
| Magnevist (Gadopentetate Dimeglumine) - PRE | Image Quality Score | Reader 2 | 1.74 units on a scale | Standard Deviation 0.44 |
| Magnevist (Gadopentetate Dimeglumine) - PRE | Image Quality Score | Reader 1 | 1.42 units on a scale | Standard Deviation 0.53 |
| Magnevist (Gadopentetate Dimeglumine) - PRE | Image Quality Score | Reader 3 | 1.99 units on a scale | Standard Deviation 0.09 |
| Magnevist (Gadopentetate Dimeglumine) - PAIRED | Image Quality Score | Reader 1 | 2.96 units on a scale | Standard Deviation 0.26 |
| Magnevist (Gadopentetate Dimeglumine) - PAIRED | Image Quality Score | Reader 3 | 2.99 units on a scale | Standard Deviation 0.09 |
| Magnevist (Gadopentetate Dimeglumine) - PAIRED | Image Quality Score | Reader 2 | 2.98 units on a scale | Standard Deviation 0.19 |
p-value: <0.001Regression, Logistic
p-value: <0.001Regression, Logistic
Secondary
Number of Lesions
The number of lesions for which observations could be made was calculated for each MRI modality and results are summarized per patient
Time frame: up to 24 hours
Population: The number of participants for analysis depended on the number of evaluable cases (PRE and PAIRED) determined by each reader. Only adult participants are included in this data set.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dotarem (Gadoterate Meglumine) - PRE | Number of Lesions | Reader 3 | 1.97 Number of lesions | Standard Deviation 2.99 |
| Dotarem (Gadoterate Meglumine) - PRE | Number of Lesions | Reader 2 | 2.29 Number of lesions | Standard Deviation 3.69 |
| Dotarem (Gadoterate Meglumine) - PRE | Number of Lesions | Reader 1 | 1.97 Number of lesions | Standard Deviation 3.16 |
| Dotarem (Gadoterate Meglumine) - PAIRED | Number of Lesions | Reader 3 | 2.46 Number of lesions | Standard Deviation 4.53 |
| Dotarem (Gadoterate Meglumine) - PAIRED | Number of Lesions | Reader 2 | 3.16 Number of lesions | Standard Deviation 5.21 |
| Dotarem (Gadoterate Meglumine) - PAIRED | Number of Lesions | Reader 1 | 2.69 Number of lesions | Standard Deviation 4.71 |
| Magnevist (Gadopentetate Dimeglumine) - PRE | Number of Lesions | Reader 1 | 1.98 Number of lesions | Standard Deviation 3.85 |
| Magnevist (Gadopentetate Dimeglumine) - PRE | Number of Lesions | Reader 2 | 2.60 Number of lesions | Standard Deviation 5.42 |
| Magnevist (Gadopentetate Dimeglumine) - PRE | Number of Lesions | Reader 3 | 2.15 Number of lesions | Standard Deviation 3.97 |
| Magnevist (Gadopentetate Dimeglumine) - PAIRED | Number of Lesions | Reader 3 | 3.97 Number of lesions | Standard Deviation 10.02 |
| Magnevist (Gadopentetate Dimeglumine) - PAIRED | Number of Lesions | Reader 2 | 4.50 Number of lesions | Standard Deviation 9.95 |
| Magnevist (Gadopentetate Dimeglumine) - PAIRED | Number of Lesions | Reader 1 | 4.19 Number of lesions | Standard Deviation 10.54 |