Dose Finding Study of Gadavist in Central Nervous System (CNS) Magnetic Resonance Imaging (MRI)

Study Overview
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Brief Summary
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The purpose of this study is to look at the safety (what are the side effects) and efficacy (how well does it work) of Gadavist when used for taking images of the brain and spine. The results of the MRI with Gadavist Injection will be compared to the results of MR images taken without contrast and with the results of the MR images taken with OptiMARK.

Detailed Description
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Safety issues are addressed in the Adverse Events section

Official Title
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Multi-center, Double-blind, Randomized, Controlled, Parallel Group, Dose Comparison Study With Corresponding Blinded Image Evaluation Following a Single Intravenous Injection of Three Different Doses of Gadobutrol 1.0 Molar (Gadavist) in Patients With Known or Suspected Focal Blood Brain Barrier Disturbances and/or Abnormal Vascularity of the Central Nervous System

Conditions
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Brain Diseases, Spinal Cord Diseases

Intervention / Treatment
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* Drug: Gadobutrol 0.03 mmol/kg BW (Gadavist, Gadovist, BAY86-4875)
* Drug: Gadobutrol 0.1 mmol/kg BW (Gadavist, Gadovist, BAY86-4875)
* Drug: Gadobutrol 0.3 mmol/kg BW (Gadavist, Gadovist, BAY86-4875)
* Drug: OptiMARK 0.1 mmol/kg BW


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with either known or highly suspected focal areas of disruption of the blood brain barrier (BBB) (eg, primary and secondary tumors, focal inflammatory or demyelinating disorders) and/or abnormal vascularity in the CNS, who are scheduled to undergo a routine contrast-enhanced MRI of the CNS. Patients with untreated brain tumors should constitute a minimum of 50% of the study population and patients with treated brain tumors will be limited to a maximum of 20% of the study population Exclusion Criteria: Is a female patient who is pregnant or nursing. Is a female of childbearing potential and did not have a negative urine pregnancy test the same day as the administration of gadobutrol or comparator treatment. Has received any investigational product within 30 days prior to enrolling in this study. Has been previously enrolled in this study or any other study using gadobutrol. Has any contraindication to the MRI examinations. Has a history of severe allergic or anaphylactoid reaction to any allergen including drugs and contrast agents. Has received any contrast agent within 24 hours prior to gadobutrol contrast administration, or is scheduled to receive any contrast agent within 72 hours after the gadobutrol study. Is considered to be clinically unstable or his/her clinical course during the study period is unpredictable (eg, due to previous surgery, acute renal failure). Has been treated with high dose (>55 cobalt Gy equivalent) photon radiation or global radiotherapy for CNS lesions at any time before entering the study. Is scheduled to receive chemotherapy or radiotherapy during the study period. Is expected or scheduled to have a change in any treatment or procedure between the comparator and gadobutrol MRIs that may alter their interpretation. Is scheduled or is likely to require a biopsy or surgery within the 72 hours after the gadobutrol MRI procedure, or is scheduled for or has undergone such interventions between the comparator and gadobutrol studies. Has severe cardiovascular disease. Has any contraindication to OptiMARK according to the package insert. Has more than 30 brain lesions detected by any prior imaging examination.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gadobutrol 0.03 mmol/kg BW (Gadavist, BAY86-4875)<br>Participant received one dose of 0.03 mmol/kg BW of Gadobutrol and one dose of 0.1 mmol/kg body weight (BW) of OptiMARK. The order in which the participants received Gadobutrol and OptiMARK was randomized. Gadobutrol was administered via a power injector at a rate of 5 mL/s followed by a 20 mL 0.9% saline flush at the same rate. | Drug: Gadobutrol 0.03 mmol/kg BW (Gadavist, Gadovist, BAY86-4875)<br>* Participant received one dose of 0.03 mmol/kg BW of Gadobutrol. Gadobutrol was administered via a power injector at a rate of 5 mL/s followed by a 20 mL 0.9% saline flush at the same rate.<br>Drug: OptiMARK 0.1 mmol/kg BW<br>* Participant received one dose of 0.1 mmol/kg BW of OptiMARK. OptiMARK was administered via a power injector at a rate of 2 mL/s followed by a 20 mL 0.9% saline flush at the same rate.<br>|
| Experimental: Gadobutrol 0.1 mmol/kg BW (Gadavist, BAY86-4875)<br>Participant received one dose of 0.1 mmol/kg BW of Gadobutrol and one dose of 0.1 mmol/kg BW of OptiMARK. The order in which the participants received Gadobutrol and OptiMARK was randomized. Gadobutrol was administered via a power injector at a rate of 5 mL/s followed by a 20 mL 0.9% saline flush at the same rate. | Drug: Gadobutrol 0.1 mmol/kg BW (Gadavist, Gadovist, BAY86-4875)<br>* Participant received one dose of 0.1 mmol/kg BW of Gadobutrol. Gadobutrol was administered via a power injector at a rate of 5 mL/s followed by a 20 mL 0.9% saline flush at the same rate.<br>Drug: OptiMARK 0.1 mmol/kg BW<br>* Participant received one dose of 0.1 mmol/kg BW of OptiMARK. OptiMARK was administered via a power injector at a rate of 2 mL/s followed by a 20 mL 0.9% saline flush at the same rate.<br>|
| Experimental: Gadobutrol 0.3 mmol/kg BW (Gadavist, BAY86-4875)<br>Participant received one dose of 0.3 mmol/kg BW of Gadobutrol and one dose of 0.1 mmol/kg BW of OptiMARK. The order in which the participants received Gadobutrol and OptiMARK was randomized. Gadobutrol was administered via a power injector at a rate of 5 mL/s followed by a 20 mL 0.9% saline flush at the same rate. | Drug: Gadobutrol 0.3 mmol/kg BW (Gadavist, Gadovist, BAY86-4875)<br>* Participant received one dose of 0.3 mmol/kg BW of Gadobutrol. Gadobutrol was administered via a power injector at a rate of 5 mL/s followed by a 20 mL 0.9% saline flush at the same rate.<br>Drug: OptiMARK 0.1 mmol/kg BW<br>* Participant received one dose of 0.1 mmol/kg BW of OptiMARK. OptiMARK was administered via a power injector at a rate of 2 mL/s followed by a 20 mL 0.9% saline flush at the same rate.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Categorical Visualization Score (CVS) | The primary visualization variables (number [no.] of lesions detected, border delineation, contrast enhancement, internal morphology) were condensed to a composite score (CVS). Each variable was considered a category; the CVS was calculated as: CVS=(No. of categories with increase over precontrast)-(No. of categories with decrease over precontrast). The possible outcomes of the CVS for a participant and each reader were in the range of - 3 to +4. The CVS was averaged across the 3 blinded readers, producing 1 mean CVS per participant. The higher the CVS, the more effective the treatment. | up to 2 hours after the injection of study medication | 
| Difference in Number of Lesions Detected in Pre-contrast and Combined Pre-/Post-contrast MRI. | Three blinded readers evaluated the unenhanced MRI sets and the combined unenhanced/gadobutrol-enhanced MRI sets to evaluate the number of lesions, which was then averaged to produce an average reader value. | up to 2 hours after the injection of study medication | 
| Assessment of Lesion Contrast Enhancement | The blinded readers assessed the degree of contrast enhancement for each lesion on a 4-point scale where 1 = no enhancement and 4 = excellent enhancement, which was then averaged to produce an average reader score. | up to 2 hours after the injection of study medication | 
| Assessment of Border Delineation | The blinded readers assessed the delineation for each lesion on a 4-point scale where 1 = none and 4 = excellent, which was then averaged to produce an average reader score. | up to 2 hours after the injection of study medication | 
| Assessment of Internal Morphology | The blinded readers assessed the degree of information available about internal morphology and structure for each lesion on a 3-point scale where 1 = poor and 3 = good, which was then averaged to produce an average reader score. | up to 2 hours after the injection of study medication | 
| Contrast to Noise Ratio (CNR) Between White and Gray Matter With Gadobutrol Perfusion MRI | CNR between white and gray matter in the perfusion imaging was defined as the signal intensity (SI) difference between white and gray matter divided by the standard deviation of the SI of white matter. An independent radiologist evaluated the gadobutrol-enhanced perfusion MRI for signal intensity. | up to 2 hours after the injection of study medication | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Accuracy Comparison of Gadobutrol Doses - Detection of Matched Lesions: Blinded Reader 1 | The percent accuracy (total number of lesions matching the comparator divided by the total number of lesions identified by gadobutrol) comparison of the 0.03 and 0.1 mmol/kg gadobutrol doses and the 0.1 and 0.3 mmol/kg gadobutrol doses using detection of all comparator-detected matched lesions was performed for blinded reader (BR) 1. | up to 2 hours after the injection of study medication | 
| Accuracy Comparison of Gadobutrol Doses - Detection of Matched Lesions: Blinded Reader 2 | The percent accuracy (total number of lesions matching the comparator divided by the total number of lesions identified by gadobutrol) comparison of the 0.03 and 0.1 mmol/kg gadobutrol doses and the 0.1 and 0.3 mmol/kg gadobutrol doses using detection of all comparator-detected matched lesions was performed for BR 2 | up to 2 hours after the injection of study medication | 
| Accuracy Comparison of Gadobutrol Doses - Detection of Matched Lesions: Blinded Reader 3 | The percent accuracy (total number of lesions matching the comparator divided by the total number of lesions identified by gadobutrol) comparison of the 0.03 and 0.1 mmol/kg gadobutrol doses and the 0.1 and 0.3 mmol/kg gadobutrol doses using detection of all comparator-detected matched lesions was performed for BR 3 | up to 2 hours after the injection of study medication | 
| Accuracy Comparison of Gadobutrol Doses - Detection of Matched Enhanced Lesions: Blinded Reader 1 | The percent accuracy (total number of lesions matching the comparator divided by the total number of lesions identified by gadobutrol) comparison of the 0.03 and 0.1 mmol/kg gadobutrol doses and the 0.1 and 0.3 mmol/kg gadobutrol doses using detection of all comparator-detected matched enhanced lesions was performed for BR 1 | up to 2 hours after the injection of study medication | 
| Accuracy Comparison of Gadobutrol Doses - Detection of Matched Enhanced Lesions: Blinded Reader 2 | The percent accuracy (total number of lesions matching the comparator divided by the total number of lesions identified by gadobutrol) comparison of the 0.03 and 0.1 mmol/kg gadobutrol doses and the 0.1 and 0.3 mmol/kg gadobutrol doses using detection of all comparator-detected matched enhanced lesions was performed for BR 2 | up to 2 hours after the injection of study medication | 
| Accuracy Comparison of Gadobutrol Doses - Detection of Matched Enhanced Lesions: Blinded Reader 3 | The percent accuracy (total number of lesions matching the comparator divided by the total number of lesions identified by gadobutrol) comparison of the 0.03 and 0.1 mmol/kg gadobutrol doses and the 0.1 and 0.3 mmol/kg gadobutrol doses using detection of all comparator-detected matched enhanced lesions was performed for BR 3 | up to 2 hours after the injection of study medication | 
| Evaluation of the Correct Diagnosis Following Gadobutrol-enhanced and Unenhanced MRI | The gadobutrol-enhanced and unenhanced MRI diagnoses of the average reader were compared to the final diagnosis. | up to 2 hours after the injection of study medication | 
| Evaluation of the Diagnostic Confidence Based on Unenhanced MRI and Combined Unenhanced and Enhanced MRI | The diagnostic confidence, the level of certainty in a diagnosis, was determined based on the average of the blinded readers. | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Quality (Uncorrected Cerebral Blood Volume [CBV]) - Blinded Reader 1 | BR 1 evaluated the visibility of the lesion(s) on the uncorrected CBV perfusion map. | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Quality (Uncorrected Cerebral Blood Volume (CBV)) - Blinded Reader 2 | BR 2 evaluated the visibility of the lesion(s) on the uncorrected CBV perfusion map. | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Quality (Uncorrected Cerebral Blood Volume (CBV)) - Blinded Reader 3 | BR 3 evaluated the visibility of the lesion(s) on the uncorrected CBV perfusion map. | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Quality (Corrected Cerebral Blood Volume (CBV)) - Blinded Reader 1 | BR 1 evaluated the visibility of the lesion(s) on the corrected CBV perfusion map. | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Quality (Corrected Cerebral Blood Volume (CBV)) - Blinded Reader 2 | BR 2 evaluated the visibility of the lesion(s) on the corrected CBV perfusion map. | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Quality (Corrected Cerebral Blood Volume (CBV)) - Blinded Reader 3 | BR 3 evaluated the visibility of the lesion(s) on the corrected CBV perfusion map. | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Quality (Cerebral Blood Flow (CBF)) - Blinded Reader 1 | BR 1 evaluated the visibility of the lesion(s) on the CBF perfusion map. | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Quality (Cerebral Blood Flow (CBF)) - Blinded Reader 2 | BR 2 evaluated the visibility of the lesion(s) on the CBF perfusion map. | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Quality (Cerebral Blood Flow (CBF)) - Blinded Reader 3 | BR 3 evaluated the visibility of the lesion(s) on the CBF perfusion map. | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Quality (Time to Peak (TTP)) - Blinded Reader 1 | BR 1 evaluated the visibility of the lesion(s) on the TTP perfusion map. | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Quality (Time to Peak (TTP)) - Blinded Reader 2 | BR 2 evaluated the visibility of the lesion(s) on the TTP perfusion map. | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Quality (Time to Peak (TTP)) - Blinded Reader 3 | BR 3 evaluated the visibility of the lesion(s) on the TTP perfusion map. | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Quality (Mean Transit Time (MTT)) - Blinded Reader 1 | BR 1 evaluated the visibility of the lesion(s) on the MTT perfusion map. | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Quality (Mean Transit Time (MTT)) - Blinded Reader 2 | BR 2 evaluated the visibility of the lesion(s) on the MTT perfusion map. | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Quality (Mean Transit Time (MTT)) - Blinded Reader 3 | BR 3 evaluated the visibility of the lesion(s) on the MTT perfusion map. | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Quality (Permeability Factor (PF) - Blinded Reader 1 | BR 1 evaluated the visibility of the lesion(s) on the PF perfusion map. | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Quality (Permeability Factor (PF) - Blinded Reader 2 | BR 2 evaluated the visibility of the lesion(s) on the PF perfusion map. | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Quality (Permeability Factor (PF)) - Blinded Reader 3 | BR 3 evaluated the visibility of the lesion(s) on the PF perfusion map. | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Parameter Value (Uncorrected Cerebral Blood Volume (CBV)) - Independent Radiologist | The independent radiologist determined the uncorrected CBV for each lesion. CBV is the volume of blood in the tissue. | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Parameter Value (Corrected Cerebral Blood Volume (CBV)) - Independent Radiologist | The independent radiologist determined the corrected CBV for each lesion. CBV is the volume of blood in the tissue. | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Parameter Value (Cerebral Blood Flow (CBF)) - Independent Radiologist | The independent radiologist determined the CBF for each lesion. CBF is the volume of blood passing through tissue per unit of time. | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Parameter Value (Time to Peak (TTP)) - Independent Radiologist | The independent radiologist determined the TTP for each lesion. TTP is the delay between the arrival of the contrast agent bolus arrival time and the peak of the concentration curve. | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Parameter Value (Mean Transit Time (MTT)) - Independent Radiologist | The independent radiologist determined the MTT for each lesion. The MTT is the time (seconds) for contrast to pass through tissues. | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Parameter Value (Permeability Factor (PF)) - Independent Radiologist | The independent radiologist determined the PF for each lesion | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Artifacts (Uncorrected Cerebral Blood Volume (CBV)) - Blinded Reader | The blinded reader evaluated if artifacts were present on the uncorrected CBV perfusion map and recorded the type of the major artifact. EPI: echo-planar imaging; T2: transversal relaxation time. | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Artifacts (Corrected Cerebral Blood Volume (CBV)) - Blinded Reader | The blinded reader evaluated if artifacts were present on the corrected CBV perfusion map and recorded the type of the major artifact. EPI: echo-planar imaging; T2: transversal relaxation time. CBV is the fraction of the tissue volume occupied by the blood. | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Artifacts (Cerebral Blood Flow (CBF)) - Blinded Reader | The blinded reader evaluated if artifacts were present on the CBF perfusion map and recorded the type of the major artifact. EPI: echo-planar imaging; T2: transversal relaxation time | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Artifacts (Time to Peak (TTP)) - Blinded Reader | The blinded reader evaluated if artifacts were present on the TTP perfusion map and recorded the type of the major artifact. EPI: echo-planar imaging; T2: transversal relaxation time | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Artifacts (Mean Transit Time (MTT)) - Blinded Reader | The blinded reader evaluated if artifacts were present on the MTT perfusion map and recorded the type of the major artifact. EPI: echo-planar imaging; T2: transversal relaxation time | up to 2 hours after the injection of study medication | 
| Evaluation of Perfusion Map Artifacts (Permeability Factor (PF)) - Blinded Reader | The blinded reader evaluated if artifacts were present on the PF perfusion map and recorded the type of the major artifact. EPI: echo-planar imaging; T2: transversal relaxation time | up to 2 hours after the injection of study medication | 
| Evaluation of MRI Tumor Grade Agreement With Biopsy Results by Dose Group | The blinded readers gave an estimation of the tumor grade of brain tumors (low grade [I or II] or high grade [III or IV]) in terms of malignancy using the information obtained by perfusion imaging, which was compared to the biopsy sample results | up to 2 hours after the injection of study medication | 
| Contrast to Noise Ratio (CNR) of Lesion/Gray Matter and Lesion/White Matter | CNR between lesion/gray matter and lesion/white matter in the perfusion imaging was defined as the signal intensity (SI) difference between lesion and gray or white matter divided by the standard deviation of background noise. An independent radiologist evaluated the gadobutrol-enhanced perfusion MRI for signal intensity. | up to 2 hours after the injection of study medication | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Contrast Agents